PK-guided Dosing Research Articles

Relationship of body mass index and plasma imatinib levels in CML patients and mitigation of clinical impact using PK-guided dosing strategy.

e18522 Background: Imatinib is a mainstay of treatment for patients with chronic myeloid lymphoma (CML). Exposure-response relationships have been demonstrated and trough levels between 800 and 1000 ng/ml are usually associated with Major Molecular Response (MMR), prolonged survival and acceptable safety. The extent to which body mass index (BMI) might influence drug pharmacokinetics (PK) and clinical outcome remains to be investigated. Methods: Therapeutic drug monitoring was performed in 60 adult patients (56 years, M33/27F) starting imatinib (400 mg QD) for CML, and baseline deviation from target Cmin was used to subsequently adjust dosing using Monolix software. Baseline BMI was calculated and collected along with other patient characteristics and comedications likely to alter imatinib PK. Response (MMR at 3 months) and drug-related toxicity (CTCAE grading) were recorded. Patients were divided into three subgroups: BMI<18.5; 18.5<BMI<24.5, and BMI>24.5. The association between BMI and trough imatinib levels at baseline, further differences in toxic events and response rate between cohorts, as well as differences in dosing after PK-guided dose adjustment, were all tested using appropriate statistical analysis. Results: Mean imatinib trough levels at baseline were 1172 (754-4737), 870 (276-1767) and 820 (334-2217) ng/ml for patients with BMI<18.5, 18.5<BMI<24.5 and BMI>24.5, respectively. Patients with BMI<18.5 were statistically overexposed (p<0.01, ANOVA). Conversely, there was a trend towards lower exposure in patients with BMI>24.5, but this was not statistically significant. Multivariate analysis confirmed that low BMI was an independent factor for overexposure with imatinib. After PK-guided dosing, a statistically significant difference in dosing after correction was observed, as overexposed patients had their dose reduced to an average of 330 mg QD, whereas underexposed patients had their dose increased to an average of 500 mg QD (p<0.01, paired t-test). Consequently, when comparing in the three different cohorts the incidence of both response and toxic events, no difference was observed among patients (p=0.33 and p=0.911 for efficacy and toxicity respectively, Chi-2 test). Conclusions: Low BMI (<18.5) puts patients at risk of significant overexposure to imatinib, whereas there is a trend towards lower exposure in patients with high BMI (>24.5). This could potentially lead to either increased toxicity or lack of efficacy is no adjustment in dosing is performed. Here, TDM with subsequent adaptive dosing helps to correct the dose according to the initial deviation from target, thus smoothing the clinical impact of the differences in exposure observed at the start of treatment.

Standard atezolizumab leads to severe overexposure in real-world patients with lung cancer: How far could we go in extending dosing intervals and saving money?

3085 Background: Immune checkpoint inhibitors are given as fixed doses, which may lead to drug exposure exceeding the plasma concentrations required for target engagement. If confirmed, this could pave the way for de-escalating treatments without compromising efficacy while reducing drug-costs. Methods: We monitored plasma concentrations of Atezolizumab in 40 real-world patients. A final set of 33 patients with SCLC or NSCLC were available for full PK/PD analysis. Individual PK parameters were derived using a population pharmacokinetics approach. Individual PK parameters allowed to simulate the full concentration-time profiles and to further simulate for each patient the time to reach the target threshold after the first dose of Atezolizumab. In addition, efficacy (RECIST criteria) and immune-related adverse events, (IRAEs, CTCAE grading) were monitored and statistical analysis was performed to search for possible exposure-response relationships. Results: Overall Response Rate was 55% and no severe IRAEs were observed. All patients had Cmin levels significantly above the target threshold on the first cycle of Atezolizumab. The mean Cmax after the first dose on cycle 1 was 426.1 µg/ml and the mean Cmin was 68.5 µg/ml, i.e. 11-time higher than the target threshold associated with target engagement (i.e., 6 µg/ml). The mean AUC at the first cycle was 4763 µg.d/ml. Exposure metrics and PK parameters at baseline and simulated prior RECIST evaluation were tested together with other covariates (i.e. age, sex, smoking, NLR, number of metastatic sites, line of treatment) as possible predictive markers of response or toxicity. None of the parameters related to Atezolizumab pharmacokinetics or exposure levels were associated with efficacy or toxicity, most likely because all patients had plasma levels well above pharmacologically active concentrations. First-line therapy was associated with better response on univariate analysis, but this effect was lost on multivariate analysis. Further simulations based on time required to fall below the efficacy threshold suggest that dosing intervals could be extended from Q7W to Q19W (mean: Q12W). Considering the annual budget for Atezolizumab at our institution, further simulations showed that the annual drug cost could thus be reduced from 2.5 M€ to 0.6 M€ while ensuring that all patients remain above active concentrations. Conclusions: Our study demonstrates in a real-world setting that standard Atezolizumab given as 1200 mg Q3W infusion leads to severe overexposure of the drug. This strong overexposure was not associated with more severe treatment-related toxicities. Finally, our study suggests that PK-guided dosing with Atezolizumab could help customizing the dosing interval while maintaining efficacious trough levels and that Q12W could be an alternate scheduling leading to significant cut in drug costs.

Abstract CT178: Phase 1 trial of PF-07799933 (ARRY-440), a next-generation BRAF inhibitor, for BRAF-mutant cancers

Abstract BACKGROUND Approved BRAF inhibitors (BRAFi) have transformed the treatment of BRAF V600-mutant cancers. However, clinical benefit is limited by BRAF dimer-promoting resistance mutations, toxicity from paradoxical activation of signaling in BRAF wild-type cells, and poor brain penetration. Further, current RAF inhibitors are ineffective against non-V600 BRAF mutants. Next-generation agents that cause pan-RAF inhibition may more broadly target BRAF mutants but are limited by a narrow therapeutic index. PF-07799933 (ARRY-440) is a brain-penetrant BRAF-selective monomer/dimer inhibitor that spares ARAF and CRAF. METHODS We characterized PF-07799933 in patient (pt)-derived BRAF-mutant cancer cells in vitro and in vivo. We investigated PF-07799933 in pts with refractory BRAF-mutant solid tumors using a novel first-in-patient phase 1 design that enabled flexible, rapid dose escalation based on safety and pharmacokinetics (PK) assessments. RESULTS PF-07799933 inhibited signaling in vitro, disrupted BRAF-containing homo- and heterodimers, and caused less paradoxical signaling than approved agents. PF-07799933 alone and in combination with binimetinib inhibited tumor growth systemically and in the brain in mouse xenografts harboring de novo and acquired BRAF dimer-forming mutations. As of August 24, 2023 data cutoff, 30 pts with BRAF-mutant cancers started PF-07799933 treatment at 50 mg QD-450 mg BID as monotherapy (60%) or combination with binimetinib (27%) or cetuximab (all colorectal cancer [CRC]) (13%). Tumor types were melanoma (mel) (43%), CRC (17%), primary brain (PBT) (13%), thyroid (10%), and other (n=1/3% each). BRAF mutations were class I (V600E) (73%), Class II (13%), and class III (13%). All BRAF V600E+ cancer pts were previously treated with ≥1 approved BRAFi and all BRAF V600E+ mel pts also were previously treated with ≥1 immune checkpoint inhibitor. PF-07799933 was well-tolerated as monotherapy or combination. There were no DLTs and the MTD was not reached. Treatment-emergent adverse events (TEAEs) in ≥3 pts for monotherapy were fatigue (any grade 44%/grade ≥3 0%), headache (28%/0%), vision blurred (22%/6%), and lipase increased (16%/0%). The most common TEAEs for combination were peripheral edema (33%/0%), acneiform rash, diarrhea, and fatigue (each 28%/0%). The AE profile was consistent with less paradoxical signaling activation. PK-guided dose escalation enabled PF-07799933 efficacious concentrations to be reached by dose level 3 (225 mg BID), together with multiple confirmed responses in BRAF V600E+ cancer pts (n=4/7 at 225 mg BID ± binimetinib, includes 1 complete response [CR] in a BRAF V600E+ PBT pt) systemically, in the brain, and all after failure of approved BRAF inhibitors. A 5th confirmed response (2nd BRAF V600E+ PBT pt) occurred after data cutoff. This includes, to our knowledge, the first evidence of efficacy in a BRAF V600E+ pt with a dimerizing BRAF splice variant. A BRAF G466E+ (class III) adenoid cystic carcinoma pt had a molecular CR in ctDNA. CONCLUSION PF-07799933 treatment was associated with anti-tumor activity against BRAF V600- and non-V600-mutant cancers preclinically and in treatment-refractory pts. The novel, rapid PK-informed dose escalation design provides a new paradigm for accelerating testing of next-generation targeted therapies early in clinical development. TRIAL REGISTRATION NUMBER NCT05355701 Citation Format: Rona Yaeger, Meredith McKean, Rizwan Haq, Joseph T. Beck, Matthew H. Taylor, Jonathan Cohen, Daniel Bowles, Shirish M. Gadgeel, Catalin Mihalcioiu, Kyriakos P. Papadopoulos, Eli L. Diamond, Keren B. Sturtz, Gang Feng, Stefanie K. Drescher, Micaela B. Reddy, Bhaswati Sengupta, Arnab K. Maity, Suzy A. Brown, Anurag Singh, Eric N. Brown, Brian R. Baer, Jim Wong, Tung-Chung Mou, Wen I. Wu, Dean Kahn, Sunyana Gadal, Neal Rosen, John J. Gaudino, Patrice A. Lee, Dylan P. Hartley, Stephen Michael Rothenberg. Phase 1 trial of PF-07799933 (ARRY-440), a next-generation BRAF inhibitor, for BRAF-mutant cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT178.

Economic evaluation of personalized vs. standard dosing of 5-fluorouracil in first-line chemotherapy for metastatic colorectal cancer in Australia.

Using pharmacokinetics (PK)-guided 5-fluorouracil (5-FU) for metastatic colorectal cancer (mCRC) improves overall survival (OS) and decreases toxicity, yet its value for money in the Australian setting is unknown. Our study assesses the cost-effectiveness of PK vs. body surface area (BSA) dosing of 5-FU for patients with mCRC. We developed a semi-Markov model with four health states to compare PK-guided dosing within a FOLFOX regimen vs. BSA-guided dosing for mCRC patients from an Australian healthcare system perspective. Transition probabilities were derived from fitted survival models, with utility values obtained directly from published studies. We calculated direct healthcare costs, quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs), and included both one-way and probabilistic sensitivity analyses. BSA-guided FOLFOX provided 1.291 QALYs at a cost of $36 379, compared with PK-guided FOLFOX which delivered 1.751 QALYs at a cost of $32 564. Therefore, PK-guided dosing emerges as the dominant strategy offering both better health outcomes and lower costs. The variables that had the greatest impact on the overall ICER were the adverse event rates in the BSA and PK groups, model time horizon, utility of progression-free survival and PREDICT assay cost. Our univariate and multivariate sensitivity analysis confirmed that the ICER for PK FOLFOX consistently remained below $50 000 per QALY across all tested variables. PK dose management of 5-FU-based chemotherapy in mCRC patients appears to be a cost-saving strategy in Australia. However, our model estimates are drawn from limited, low-quality evidence. Further evidence from randomized controlled trials (RCTs), directly comparing PK-based to BSA-based dosing across a variety of current regimens, is needed to address our model's uncertainties.

Identifying Ideal Individuals for PK-Guided Dosing; Recreational Risks and Elevated Breakthrough Bleeding

Introduction PK-guided dosing is a useful tool for personalized FVIII prophylaxis for people living with Hemophilia A (PwHA). While many individuals can benefit from this intervention, certain subsets of the population of PwHA may see increased benefit and be considered ideal candidates for PK-guided dosing. We aim to identify sub-populations of interest who may have increased benefit of PK-guided dosing, namely those with high levels of bleeding risk from recreational activity, and PwHA with elevated levels of bleeding. Clinical and FVIII utilization outcomes are analyzed in these cohorts to determine if these populations have increased benefit from PK-guided dosing. Methods Based on a retrospective study of 132 PwHA with moderate to severe Hemophilia A (FVIII < 5%) to determine effects of PK-guided dosing on clinical and utilization outcomes (Young, 2022), 58 matched criteria for undergoing a PK for optimization of therapy with a given product. Individuals were stratified by recreational activity risk using a modification of the National Hemophilia Foundation's activity risk scale (Anderson, 2017, p. 22), grouping individuals into mild, moderate, and high recreational activity risk for bleeding. Bleeding rates prior to PK assessment were calculated, and individuals were classified into groups based on pre-index annualized bleed rate (ABR) ≥ 3 and pre-index ABR < 3, due to bimodal distribution. Index date was defined as date of the PK-guided prescription. Results Recreational activity risk was available for 56/58 individuals, and after PK-guided dosing 53/56 had no change in activity level. Analyses were limited to these 53, 28 with mild risk, 19 with moderate risk, and 6 with high risk. Individuals with high activity risk had severe Hemophilia A (FVIII < 1%), and had median age of 12 years (IQR: 12-17) at PK-guidance. Overall mean pre-index ABR was 3.6 (sd: 4.2), with majority of bleeds associated with joint or traumatic bleeds. High activity risk individuals had higher traumatic ABR prior to index date compared to those with low or moderate activity risk. Soccer was the most common high risk activity reported by 4/6 individuals (66.7%), with tackle football and martial arts reported in the remaining individuals. Individuals with mild/moderate risk did not differ from those with high activity risk by age, hemophilia severity, number of target joints, or pre-index ABR. Within these groups, we found significant decreases in ABR after PK-guidance among those with mild risk (-2.6 [95% CI:-4.4, -1.0]), driven by decrease in joint (-1.7 [-3.2, -0.4]) and traumatic (-1.2 [-2.2, -0.3]) bleeds. Similar trends were observed in high activity risk group for overall ABR ( -2.2 [-4.8, 0.4]), joint bleeds (-1.6 [-4.0, 0.2]) and traumatic bleeds (-1.1, [-2.4, 0.4]) but limited sample increased uncertainty of estimates. No change in ABR was identified for those with moderate activity risk. No major difference in mean weekly consumption (MWC) after PK guidance was observed in those with mild risk (+3.6 IU/kg [-6.2, 13.3]), but those with high risk trended towards increase in MWC (+11.0 IU/kg [-4.8, 26.7]) of FVIII for prophylaxis. Annualized cost of FVIII prophylaxis similarly trended towards increase in those with high activity risk (+$49270 [-$24698, $123237]). High levels of pre-index ABR was identified in 25/58 individuals with mean pre-index ABR of 8.2 (sd: 5.6). Individuals with high reported bleeding prior to PK-guidance were median 13 years (IQR: 8-20) of age at PK-guidance, with 88% having severe Hemophilia A. Significant decreases in ABR were observed after PK-guidance (-5.3 [95% CI: -7.2, -3.2]), driven by decrease in joint and traumatic bleeds. Significant increases in MWC (+18.11 IU/kg [7.0, 29.2]) and annualized cost (+$45783 [$17943, $73624]) of prophylaxis were observed in these individuals. Although quantity of FVIII used to treat breakthrough bleeds was not captured in this study, use of on-demand FVIII likely decreased with lower observed ABR. Conclusion Individuals with elevated bleeding levels are prime candidates for PK-guided dosing, with significantly lower bleeding rates observed after PK-guided dosing, leading to improved quality of life and decreased risks of joint degeneration. While sample was limited, individuals with high activity risk appear to benefit from PK-assessment as well, to attain increased bleed protection during recreational activities in spite of inherent risks.

A Novel, Rapid, and Accurate Quantitative Hydroxyurea Assay

Introduction: Hydroxyurea is a highly effective treatment for children and adults with sickle cell anemia (SCA) and is now considered standard-of-care therapy in high-resource countries. There is wide interpatient variability in the optimal dose, which is defined as the daily dose that provides maximal induction of protective fetal hemoglobin to decrease erythrocyte sickling while causing only mild marrow suppression. The time and cost of hydroxyurea dose titration are barriers to its widespread use in low-resource settings. The titration process required to identify an optimal dose can be abbreviated by measuring individualized hydroxyurea pharmacokinetics (PK) to guide personalized precision dosing, which could be especially useful in low-resources settings with limited laboratory monitoring. However, measurement of hydroxyurea in serum and other physiological fluids is not commonly performed during routine clinical treatment. Current methodology to quantify hydroxyurea concentrations requires complex and time-consuming chemical derivatization followed by detection by colorimetric spectrophotometry, high performance liquid chromatography (HPLC), or liquid chromatography mass spectrometry (LC-MS). To consider performing PK-guided dosing in low-resource settings, a simple, accurate, and efficient hydroxyurea assay is needed. Methods: A commercially available open-system HPLC unit for hemoglobin separation (SmartLifeLC, PolyLC Inc, Columbia MD) was equipped with a 3.5-micron, 4.6 mm × 50 mm Zorbax Eclipse XDB-C18 column with matching guard column (Agilent Technologies, Santa Clara, CA); mobile phases of 46% methanol and 100% acetonitrile; and a 200-600nm multi-wavelength detector. The chemical derivatization process was modified from previously published techniques that use xanthydrol (Sigma-Aldrich, St. Louis MO) for detection of primary amides. N-methylurea (Sigma-Aldrich) was included as an internal standard. Hydroxyurea (Sigma-Aldrich) was diluted in whole blood collected from healthy controls to create a calibration curve encompassing the typical pharmacological range of hydroxyurea at 80, 40, 20, 10, and 5 mg/mL. Quality Control (QC) samples were prepared at 50, 25, 12.5, and 6.25 mg/mL to validate the calibration curve before testing patient samples. Blood was applied to 20mL volumetric absorptive microsampling devices (Mitra, Trajan Scientific and Medical, Torrance CA) and dried for future elution and analysis. HPLC results were compared to LC-MS results to assess accuracy. Results: Blood was eluted from the Mitra microsampling device and derivatized in a xanthydrol solution before HPLC analysis. Using a 10-minute run with 210nm wavelength detection, the xanthydrol-modified hydroxyurea reproducibly yielded a linear calibration curve with r 2 >0.95 (Figure), and the actual concentrations were within 20% of the theoretical values. Repeated testing of control and patient samples revealed a typical intra-day coefficient of variation <15% and inter-day coefficient of variation <20%. The agreement between nominal values and assay results determined for a wide range of QC samples from both methods exceeded the FDA-recommended threshold of 67% for chromatographic assay validation with 86% agreement on LC-MS and 85% with the new method. The entire elution and derivatization procedure could be completed using dried Mitra blood samples in less than 60 minutes. Conclusions: Quantitative hydroxyurea measurement of blood or serum can now be accomplished using a novel, rapid, HPLC technique that features xanthydrol-based derivatization of hydroxyurea, an internal standard, and UV wavelength detection. This technique is accurate, reproducible, and relatively simple, and thus deemed suitable for hydroxyurea concentration measurements needed for PK-guided dosing calculations for children with SCA living in low-resource settings. This novel technique will be added to the multi-country Realizing Effectiveness Across Continents with Hydroxyurea (REACH, NCT01966731) trial that will feature PK-guided precision dosing for young children with SCA starting hydroxyurea treatment.

Pharmacokinetic-Guided Hydroxyurea to Reduce Transfusion Requirements in Ugandan Children with Sickle Cell Anemia: Baseline Data from the Alternative Dosing and Prevention of Transfusions (ADAPT) Trial

Background: Children are the primary recipients of blood transfusions in sub-Saharan Africa where the demand for safe blood far exceeds the supply. Without disease-modifying therapy, sickle cell anemia (SCA) causes excess morbidity, mortality, and healthcare resource utilization, specifically requiring a high reliance on blood transfusions. Hydroxyurea is a safe and effective medication for the treatment of SCA that decreases blood transfusion use in this population, which may offset the costs of improving hydroxyurea access. The widespread use of hydroxyurea in Africa is limited in part by challenges determining an individual's optimal dose; pharmacokinetic (PK) dosing of hydroxyurea may streamline the dosing process, maximizing the clinical benefits and minimizing toxicities. We designed the Alternative Dosing And Prevention of Transfusions (ADAPT) trial to analyze the reduction in transfusion use with hydroxyurea and as a pilot evaluation of the feasibility of PK-guided hydroxyurea dosing in Uganda. Methods: ADAPT (NCT05662098) is a prospective, single-center, open-label cohort study at Jinja Regional Referral Hospital in Uganda. Children 1-10 years old with HbSS were eligible to enroll; those already receiving hydroxyurea or scheduled blood transfusions, or with malignancy, HIV, tuberculosis, or other chronic illnesses were excluded, and those who received a transfusion within 30 days were temporarily excluded. All participants completed a 3-month screening period during which they underwent baseline evaluations and hydroxyurea PK testing. For PK testing, a 500 mg hydroxyurea test dose was administered, and serum was collected 30, 60, and 180 minutes after the dose. Hydroxyurea concentrations were determined via chemical derivatization and high-performance liquid chromatography in Uganda. Area-under-time-concentration-curves (AUC) and Bayesian estimation were then used to calculate the optimal hydroxyurea dose based on target medication exposure. Those for whom hydroxyurea PK evaluation was completed successfully with a dose recommendation between 15-35 mg/kg/day started on their PK-guided hydroxyurea dose; otherwise, participants started on the default dose of 20 mg/kg/day. All participants will be treated on hydroxyurea for a minimum of 12 months during which time both treatment groups will follow the same laboratory monitoring and dose adjustment protocol to achieve the maximum tolerated dose. The primary study endpoint is the incidence rate ratio of blood transfusion use during screening versus treatment. Secondary endpoints include characterization of blood transfusions (indications, risk factors, adverse reactions), feasibility of PK testing, and laboratory and clinical adverse events comparing children started on PK-guided versus default dosing. Results: From June 2022 to January 2023, 106 participants were enrolled, exceeding the projected enrollment pace and goal. The average age (mean ± SD) at enrollment was 4.6 ± 2.3 years, and 50% were female. Per family-reported history, most participants had previously received a blood transfusion (78%) with 15% reporting at least 6 lifetime transfusions. Five percent had a prior stroke. A majority also had a history of pain events (86%), malaria (79%), and dactylitis (74%). Only 2% had previously used hydroxyurea. At enrollment, the median weight-for-height z-score was -0.19 (interquartile range -1.03-0.32), and baseline exam demonstrated a palpable spleen in 20%. Abdominal ultrasonography was completed on all participants, and the spleen was identified in 75% of participants with a mean volume of 132 ± 99 mL. Transcranial Doppler exams were completed on 105 participants (99%) during screening with 13% conditional and 6% abnormal results. Baseline labs (mean ± SD) documented hemoglobin = 7.7 ± 1.3 g/dL and HbF = 10.3 ± 7.1 %. Of 106 children enrolled, 1 died from acute chest syndrome in screening and 2 were withdrawn after moving away from the clinic; 103 successfully initiated hydroxyurea treatment. Conclusion: ADAPT has fully completed enrollment and will prospectively evaluate the effectiveness of hydroxyurea treatment on reducing transfusion use in Ugandan children with SCA, a finding with both individual and public health implications. ADAPT will also provide pilot data regarding the feasibility of PK-guided dosing of hydroxyurea to facilitate safe, effective hydroxyurea use in Africa.

The CetuxIMAX protocol: a non-interventional, uncontrolled, and non-comparative multicentric study for exploring the pharmacokinetics/pharmacodynamics relationships of cetuximab in head and neck cancer patients

Background: In a previous pilot-study, a link between Cetuximab exposure levels (i.e., trough levels above 34 mg/ml) and clinical outcome in head and neck cancer patients was found. Considering the high inter-individual variability in Cetuximab plasma levels, lack of efficacy could thus be linked to inadequate exposure levels, rather than issues with signalling pathways at the tumor level. Methods: The CetuxIMAX study is a non-interventional, uncontrolled, and non-comparative multicentric study in patients with recurrent or metastatic head and neck squamous cell carcinoma, and treated by any Cetuximab-based regimen. A total of 122 patients will be enrolled in this study. The primary endpoint is the estimation of receiver operating characteristic (ROC) and area under the ROC curve (AUROC) of Cetuximab trough plasma level for the disease control rate (DCR). Pharmacokinetics samples will be collected at first cycle, when steady-state is reached, and during maintenance phase to monitor the Cetuximab levels throughout time. Standard PK modelling using population-approach will be performed to identify individual PK parameters and enable further simulations of exposure levels throughout the different cycles. Univariate and multivariable statistical analysis aiming at exploring any association between Cetuximab exposure levels and clinical outcome will be performed. Conclusions: Should the target therapeutic window associated with efficacy be confirmed with Cetuximab in head/neck cancer patients, this could pave the way for PK-guided dosing next. Based upon single point PK sampling, pop-PK modelling could help personalizing dosing or scheduling, to ensure an optimal toxicity-efficacy ratio with Cetuximab. Trial Registration: Trial registration number is NCT 04218136.

Hydroxyurea pharmacokinetics and precision dosing in low-resource settings.

Introduction: Hydroxyurea is effective disease-modifying treatment for sickle cell anemia (SCA). Escalation to maximum tolerated dose (MTD) achieves superior benefits without additional toxicities, but requires dose adjustments with serial monitoring. Pharmacokinetic (PK)-guided dosing can predict a personalized optimal dose, which approximates MTD and requires fewer clinical visits, laboratory assessments, and dose adjustments. However, PK-guided dosing requires complex analytical techniques unavailable in low-resource settings. Simplified hydroxyurea PK analysis could optimize dosing and increase access to treatment. Methods: Concentrated stock solutions of reagents for chemical detection of serum hydroxyurea using HPLC were prepared and stored at -80C. On the day of analysis, hydroxyurea was serially diluted in human serum, then spiked with N-methylurea as an internal standard and analyzed using two commercial HPLC machines: 1) standard benchtop Agilent with 449nm detector and 5 micron C18 column; and 2) portable PolyLC with 415nm detector and 3.5 micron C18 column. After validation in the United States, the portable HPLC and chemicals were transported to Tanzania. Results: A calibration curve using hydroxyurea 2-fold dilutions ranging from 0 to 1000µM was plotted against the hydroxyurea:N-methylurea ratio. In the United States, both HPLC systems yielded calibration curves with R2 > 0.99. Hydroxyurea prepared at known concentrations confirmed accuracy and precision within 10%-20% of the actual values. Both HPLC systems measured hydroxyurea with <10% variance from the prepared concentrations, and paired analysis of samples on both machines documented <15% variance. Serial measurements of 300 and 100μM concentrations using the PolyLC system were precise with 2.5% coefficient of variance. After transport to Tanzania with setup and training, the modified PolyLC HPLC system produced similar calibration curves with R2 > 0.99. Conclusion: Increasing access to hydroxyurea for people with SCA requires an approach that eases financial and logistical barriers while optimizing safety and benefits, especially in low-resource settings. We successfully modified a portable HPLC instrument to quantify hydroxyurea, validated its precision and accuracy, and confirmed capacity building and knowledge transfer to Tanzania. HPLC measurement of serum hydroxyurea is now feasible in low-resource settings using available laboratory infrastructure. PK-guided dosing of hydroxyurea will be tested prospectively to achieve optimal treatment responses.

DosEmi study protocol: a phase IV, multicentre, open-label, crossover study to evaluate non-inferiority of pharmacokinetic-guided reduced dosing compared with conventional dosing of emicizumab in people with haemophilia A

IntroductionEmicizumab effectively prevents bleeding in people with haemophilia A (PwHA), but is a burden for national healthcare budgets and consequently may limit access. According to the drug label, dosing of...

Individualized, PK-Guided Dosing of Hydroxyurea Is Not Associated with Increased Hematologic Toxicity Compared to Weight-Based Initial Dosing: Interim Results from the Hops Trial

Introduction: Initiation of hydroxyurea (HU) in the first year of life is becoming an increasingly accepted standard of care for children with sickle cell anemia (SCA). Stepwise dose escalation to maximum tolerated dose (MTD) typically starts empirically at 20 mg/kg/day, based on early studies of adults and the subsequent BABY HUG study. However, recent results from the NOHARM trial in Uganda demonstrated the clinical superiority and similar safety profile of a higher initial dose (25 mg/kg with dose escalation) compared to fixed 20 mg/kg dosing. Despite these findings, many providers remain hesitant to start at doses higher than 20 mg/kg/day, mostly related to possible hematologic toxicity. Similarly, there is great variability in dose escalation strategies and variation in laboratory thresholds used to decide whether to hold or dose escalate HU therapy. Study Design and Rationale: Recognizing the significant interpatient variability in dosing and the importance in optimizing exposure, we have developed an individualized, pharmacokinetics (PK)-guided dosing strategy of HU for children with SCA. The single center TREAT trial demonstrated that an individualized dosing strategy, using higher starting doses (27.7 ± 4.9 mg/kg/day) was feasible and effective, achieving MTD almost immediately and HbF ≥30% for most patients. To further validate these results, the follow-up Hydroxyurea Optimization through Precision Study (HOPS, NCT03789591) is a randomized, multicenter trial comparing standard, weight-based initial dosing with conventional dose-escalation vs. PK-guided initial dosing for children with SCD as they initiate HU therapy. Participants (ages 6 months through 21 years), recruited from 15 pediatric sickle cell centers across the US, are randomized to receive HU either using a starting dose of 20 mg/kg/day or a PK-guided dose. Participants in both arms subsequently use the same dose adjustment strategy, more aggressive than historical dosing strategies to optimize clinical response (See Table). The primary endpoint is clinical response defined by %HbF measured 6 months after starting HU. As recruitment for the HOPS Trial is nearly complete but ongoing, we do not report primary or clinical results here. Here we demonstrate the feasibility of a PK-guided dosing across multiple centers and present data related to HU dosing and laboratory toxicity to demonstrate the safety of higher starting doses for young children with SCA. Results: As of August 1, 2022, there have been 95, of a planned 104, participants enrolled in the HOPS Trial. The median age of enrollment was 10 months with most (72%) participants ≤ 2 years of age. Despite the young starting age, most participants had at least one complication or hospitalization related to SCA prior to starting HU, and 84% demonstrated significant hemolytic anemia, evidenced by a hemoglobin < 10.5 g/dL with absolute reticulocyte count > 150 x109/L prior to initiation of HU. The mean starting absolute neutrophil count (ANC) across this entire, mostly young cohort was relatively low (3.5 ± 2.2 x 109/L) with 52% of participants having a baseline ANC < 3.0x109/L and 24% with an ANC < 1.5 x 109/L prior to hydroxyurea initiation. The starting doses were higher, as expected, for the PK-guided dosing arm (28.2 ± 5.2 mg/kg/day) compared to the weight-based dosing arm (20.2 ± 0.6 mg/kg/day). Despite high starting doses, there was no evidence of increased hematologic toxicity through the first 12 months of hydroxyurea therapy in the PK-guided dosing arm. To date, there have been a total of 24 dose holds in 18 participants due to hematologic toxicity, most commonly transient incidental neutropenia, with no differences between starting dose (i.e. higher or lower PK-guided dose) or study arm assignment (10 in PK-guided arm, 8 in weight-based arm). ANC was lower in the PK-guided dosing arm at month 6 compared to the weight-based dosing arm (2.2 ± 1.4 vs. 3.2 ± 1.9) but not in an unsafe range. Conclusions: These preliminary results from the HOPS Trial demonstrate that starting doses of hydroxyurea as high as 25-30 mg/kg/day are safe and not associated with an increased risk of clinically significant hematologic toxicity in young children with SCA, even among young children with relatively low ANCs. Complete results of the HOPS trial are forthcoming. Which will formally evaluate the clinical benefits of PK-guided initial dosing compared to the traditional 20 mg/kg starting dose strategy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Hydroxyurea Pharmacokinetics and Fetal Hemoglobin Response in Ugandan Children with Sickle Cell Anemia

Introduction Over 300,000 infants are born with sickle cell anemia (SCA) in Africa every year, and the under-5 mortality of this population is estimated to be 50-90% without treatment. Hydroxyurea is a safe, oral medication that decreases morbidity and mortality in SCA by increasing protective fetal hemoglobin (HbF) production and reducing inflammation. Hydroxyurea dosing to maximum tolerated dose (MTD) offers the optimal treatment with greatest laboratory responses and clinical benefits. Patients have variable hydroxyurea absorption and elimination rates, so the traditional approach to determining MTD is through incremental dose escalation to achieve mild myelosuppression and reduction in absolute neutrophil count (ANC). In the United States, pharmacokinetic (PK)-guided dosing of hydroxyurea for children with SCA has been shown to decrease time to MTD and to augment treatment responses, with most patients achieving over 30% HbF. Maximizing clinical benefits and minimizing logistical burdens of dosing hydroxyurea would be advantageous for areas with high SCA prevalence, but PK parameters of African children with SCA who might have higher rates of malnutrition, infections, and organ damage that affect drug absorption, distribution, and clearance are yet to be determined. Here we describe hydroxyurea PK exposure-response in Ugandan children with SCA from the Optimizing Hydroxyurea Therapy in Children with Sickle Cell Anemia In Malaria Endemic Areas: The NOHARM MTD Study (NOHARM MTD, NCT03128515). Methods NOHARM MTD was a randomized controlled trial that compared dosing strategies between hydroxyurea at fixed, weight-based dosing (~20 mg/kg/day) and dose escalation to MTD in children with SCA living in Uganda. NOHARM MTD participants underwent PK testing after 18 months of treatment. Children were administered their prescribed hydroxyurea dose in the morning at clinic, and blood was obtained by fingerstick using Mitra® microsampler devices after 20, 60, and 180 minutes. The microsampler devices were frozen at -80C in Uganda and then transported to Cincinnati Children's Hospital for analysis of hydroxyurea concentration via liquid chromatography with tandem mass spectrometry. Using our previously published population PK model, individual hydroxyurea exposures expressed as area-under-the-curve (AUC) were generated by Bayesian estimation using the PK modeling software NONMEM (Version 7.5, ICON Development Solutions, Ellicott City, USA). A hydroxyurea exposure-response analysis was completed with HbF% as the primary pharmacodynamic outcome. Results A total of 90 NOHARM MTD participants completed PK testing; samples from 12 were excluded from full analysis due to an elevated baseline concentration suggesting the participant already received the daily hydroxyurea dose before PK testing (9), supraphysiologic concentration (1), or mislabeling (2). PK profiles were analyzed for the remaining 78 participants (mean age 6.5 years, SD 0.9); of these, 41 were on fixed dose hydroxyurea and 37 were at MTD with mean doses of 18.7 mg/kg/day (SD 1.6) and 28.3 mg/kg/day (SD 4.3), respectively (Table). Those at MTD had a higher AUC with a significantly higher %HbF (mean 19% HbF on fixed dose vs 29% at MTD, p=0.0002) and lower ANC (mean 4.7 x109/L at fixed dose vs 3.2 at MTD, p=0.0045). Eighteen participants (23%) had malnutrition with a body mass index Z-score less than -1.0, and 12 (15%) participants had renal hyperfiltration with an estimated glomerular filtration rate over 150 mL/min/1.73m2; neither condition was associated with differences in AUC. Conclusion This study demonstrates the feasibility of collecting hydroxyurea PK data with timed, sparse sampling in Uganda, and the exposure-response analysis confirms that higher hydroxyurea exposure in Ugandan children with SCA is associated with greater induction of protective HbF and reduction in ANC. Malnutrition and glomerular hyperfiltration did not affect hydroxyurea exposure in this cohort. Further studies of PK-guided dosing to optimize response and time to response in this population are needed. Future directions include building capacity for local analysis of hydroxyurea concentrations using HPLC technology, real-time dose calculation via a PK model-informed algorithm, and prospective evaluation of PK-guided dosing. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Evaluation of Dosage and Food Effect on L-Glutamine Exposure for Sickle Cell Anemia: A Population Pharmacokinetic Analysis

Introduction: L-glutamine (Endari®) is an amino acid approved for the treatment of sickle cell disease (SCD). The mechanism of action of L-glutamine in SCD is not fully understood but believed to involve, at least partly, augmentation of the de novo synthesis of intracellular glutathione, which can protect sickle erythrocytes from oxidant injury. As an endogenous compound, the pharmacokinetics (PK) of L-glutamine have not been extensively studied, and currently recommended dosing is based on single-dose studies. It is also unclear how physiology, food intake, and dose impact L-glutamine drug exposure in patients with SCD. Our objective was to understand the PK of multiple dose L-glutamine therapy using a population PK analysis to identify factors that may inform optimal dosing of L-glutamine in children and adults with SCD. Methods: A total of 400 L-glutamine plasma concentration-time data points collected from 12 participants (NCT04684381) were available for population PK analysis. Each participant received 3 ascending oral doses (0.1 and 0.3 g/kg given BID and 0.6 g/kg given once daily) during a four-week study. Plasma L-glutamine and other amino acid levels were obtained before and after oral L-glutamine doses at each visit and quantified by ion exchange chromatography. Population PK analysis was performed using nonlinear mixed effect modeling by NONMEM 7.4 (ICON, Ellicott City, MD, USA). Multiple base model structures including one-compartment and two-compartment models were explored to describe the L-glutamine PK. In addition to the primary PK parameters clearance (CL/F) and volume of distribution (V/F), a relative bioavailability (F) was included in the modeling to account for the potential impact of dose and food on L-glutamine PK. Patient demographics and laboratory data, including body weight, body surface area, age, serum creatinine levels, urine creatinine levels, baseline glutamine level, meal intake, and dosages were evaluated as potential covariates using the stepwise selection method. The change in the objective function value (OFV) between two nested models was assumed to follow the χ2 distribution and was tested at a significance level of <0.01 (-6.64 points in OFV). The final model was evaluated by goodness-of-fit (GOF) plots and visual predictive check (VPC) analysis. For the VPC analysis, one thousand replicates of simulated datasets were generated using the final model, and the distribution of simulated observations was compared with the actual observations. Results: A one-compartment with first-order absorption model best described the oral dose L-glutamine concentration-time profiles. The data did not support the inclusion of a lag time in drug absorption, which is consistent with the observed rapid absorption. In accordance with allometric theory, body size was found to be significantly correlated with glutamine oral clearance (CL/F; where F represents bioavailability, which is not measured and therefore unknown) and volume of distribution (V/F). We therefore used allometrically scaled body weight to account for differences in body size. Dose-normalized peak concentration (Cmax) decreased with dose escalation (Figure 1), indicating capacity-limited, non-linear PK of oral L-glutamine. Covariate analysis identified that baseline glutamine levels and dosages negatively correlated with glutamine clearance, whereas food intake did not significantly impact glutamine clearance. Higher doses decreased the relative bioavailability of oral glutamine, again indicating a non-linear saturable absorption. Model evaluation indicated no systemic bias (Figure 2). The estimates of L-glutamine oral clearance and volume of distribution were 66 L/h/70 kg and 140 L/70 kg, respectively. Conclusions: This is the first report of a population PK analysis of L-glutamine in patients with SCD. We identified that higher baseline glutamine levels and higher doses were associated with lower L-glutamine clearance. In addition, increased doses reduced relative bioavailability, indicating that higher doses (>0.3 g/kg) may not provide higher drug concentrations. Food intake did not have a significant influence on glutamine clearance, implying that L-glutamine can be taken with or without food. Our findings will help to inform optimized dosing of L-glutamine for patients with SCD and potentially permit individualized PK-guided dosing to maximize treatment benefits. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The Impact of Pharmacokinetic-Guided Prophylaxis on Clinical Outcomes and Healthcare Resource Utilization in Hemophilia A Patients: Real-World Evidence from the CHESS II Study.

BackgroundUsing a pharmacokinetic (PK)-guided approach to personalize the dose and frequency of prophylactic treatment can help achieve and maintain targeted factor VIII (FVIII) trough levels in patients with hemophilia A.ObjectiveInvestigate clinical and healthcare resource use outcomes in patients with hemophilia A treated with or without PK-guided prophylaxis using data from the Cost of Haemophilia in Europe: A Socioeconomic Survey (CHESS) II database.MethodsCHESS II was a cross-sectional, retrospective, burden-of-illness study incorporating data from eight European countries. Patients were eligible for this analysis if they were male, ≥18 years of age, and diagnosed with congenital hemophilia A of any severity. The clinical endpoints included annualized bleeding rate (ABR), presence and number of problem/target joints, and occurrence of joint surgeries. Healthcare resource utilization endpoints included the number of hematologist consultations and bleed-related hospitalizations or emergency department admissions. Data from November 2018 to October 2020 were included and were stratified according to treatment regimen and use of PK-guided dosing.ResultsAltogether, 281 patients on prophylaxis had available FVIII trough level data. Mean (SD) age was 35.7 (13.8) years. A specific FVIII trough level was targeted in 120 (42.7%) patients and 47 (39.2%) received PK-guided dosing. Patients receiving PK-guided dosing had a mean (SD) ABR of 2.8 (2.1) and target joint number of 0.5 (0.7), compared with 3.9 (2.7) and 0.9 (1.4), respectively, for patients receiving non–PK-guided treatment. The mean (SD) number of hematologist consultations was 7.1 (5.3) for patients receiving PK-guided dosing versus 10.7 (5.7) for those who were not. A higher proportion of patients in the non–PK-guided group required hospitalization during their lifetime compared with the PK-guided group.ConclusionThis analysis of real-world data suggests that PK-guided dosing for prophylaxis has a beneficial impact on clinical and healthcare resource utilization outcomes in patients with hemophilia A.

O-12: BUILDING LOCAL CAPACITY FOR HYDROXYUREA PHARMACOKINETICS AND PRECISION DOSING IN LOW-RESOURCE SETTINGS

Purpose: Hydroxyurea is a highly effective disease-modifying treatment for sickle cell anemia (SCA) and designated an Essential Medicine by the WHO. Increasing access to hydroxyurea for SCA in low-resource settings is advocated, but the ideal approach to dosing and monitoring is debated. Escalation to maximum tolerated dose (MTD) achieves superior benefits without additional toxicities but requires incremental dose adjustments with serial monitoring. Pharmacokinetic (PK)-guided dosing uses a test dose and sparse blood sampling to model hydroxyurea metabolism and predict a personalized optimal dose, which should require fewer clinical visits, lab assessments, and dose adjustments. Currently PK-guided dosing requires expensive, complex analyses that are unavailable in low-resource settings. A simplified method for hydroxyurea PK analysis, coupled with a user-friendly dosing algorithm, could simplify dosing and monitoring. Materials and methods: Concentrated stock solutions of reagents for chemical detection of serum hydroxyurea using high performance liquid chromatography (HPLC) were stored at -80C. On the day of analysis, hydroxyurea was serially diluted in human serum, then spiked with N-methylurea as an internal standard. After deproteination with trichloroacetic acid, a Fearon reaction to detect the urea moiety was performed with diacetylmonoxime, ferric chloride, sulfuric acid, and phosphoric acid. Thiosemicarbazide was added to minimize photolability of the colored product, which was analyzed using two commercial HPLC machines: (1) a standard benchtop Agilent HPLC system with a 449nm detector and 4.6mm x 250mm, 5 micron Zorbax Eclipse XDB-C18 column; and (2) a portable PolyLC SmartLife HPLC system with a 415nm detector and 4.6mm x 50mm, 3.5 micron Zorbax column XDB-C18 column (Figure 1). The mobile phases were acetonitrile and water. After validation in the US, the portable HPLC and chemicals were transported to Tanzania for repeat analyses. Results: A calibration curve was generated using the concentration of hydroxyurea dilutions ranging from 0mM to 1000mM, plotted against the hydroxyurea:N-methylurea ratio, and both HPLC systems yielded calibration curves with R2>0.99 (Figure 1). A separate stock of hydroxyurea was diluted to create known concentrations for analysis using the calibration curve, to confirm accuracy and precision within 10-20% of the known value. Both HPLC systems measured hydroxyurea concentrations with <10% variance from the prepared concentration. Paired analysis of samples on both machines yielded results with <15% variance. Serial measurements of a standard 100 mM concentration using the PolyLC system were precise with a 2.5% coefficient of variance. After transport to Tanzania, setup, and training, the SmartLife HPLC system was able to produce similar excellent hydroxyurea concentration calibration curves with R2>0.99. Conclusion: Improving access to hydroxyurea as an essential treatment for all children living with SCA requires an approach that eases financial and logistical barriers while optimizing safety and benefit, especially in low-resource settings. We modified a portable HPLC instrument to detect hydroxyurea, validated its precision and accuracy, and confirmed capacity building and knowledge transfer to a low-resource setting. Implementation of HPLC for measurement of serum hydroxyurea concentrations is now feasible in low resource settings using available laboratory infrastructure. PK-dosing of hydroxyurea may soon be possible, with initial treatment using a personalized optimal dose.Agilent (unmodified) and SmartLife (modified) HPLC instruments for measuring serum hydroxyurea concentrationsCalibration curve of 0-1000 µM hydroxyurea measured with SmartLife PolyLC high performance liquid chromatography system demonstrating excellent R2 value in both the US (A) and Tanzania (B). The authors do not declare any conflict of interest

Abstract 1144: A multiplex LC-MS/MS method for assaying mAbs in oncology: Application to the CETUXIMAX GPCO-Unicancer trial on cetuximab pharmacokinetics in head and neck cancer patients

Abstract Implementing PK-guided dosing with monoclonal antibodies (mAbs) in oncology has been for long impaired by difficulties in developing appropriate (i.e., time- and cost-effective) bioanalytical methods suitable for routine Therapeutic Drug Monitoring, plus concerns regarding the exact PK/PD relationships of several biologics possibly blurred by the TMDD phenomenon. To help lifting these issues, we have developed and cross-validated a multiplex LC-MS/MS method allowing to assay simultaneously up to 8 mAbs in plasma, including several immune checkpoint inhibitors (i.e., atezolizumab, bevacizumab, cetuximab, ipilimumab, nivolumab, pembrolizumab, rituximab, trastuzumab). Using a ready-to-use kit (mAbXmise), the method proved to be simple and rapid - covering a concentration range of 2-100 µg/ml, in line with plasma concentrations usually expected with mAbs. Inter and intra-assay precision were both &amp;lt;15% and accuracy was comprised between 90.1 and 111.1%, thus meeting the requirements of current EMA guidelines for validating bioanalytical methods. Cross-validation using reference LC-MS/MS or ELISA methods was performed on 7 mAbs (excluding atezolizumab since no reference method was available) with a satisfactory mean absolute bias of 10.6% (3.0-19.9%). This LC-MS/MS method was next used as part of the Cetuximax trial (NCT-04218136), an open, non-randomized, single arm, multicentric study aiming at determining the PK/PD relationships of Cetuximab in Head-and-Neck cancer patients with monitoring of both Cmax and Cmin levels. Patients are all treated with the 250 mg/m² QW schedule. Previous works have suggested that Cetuximab trough levels &amp;lt; 34 µg/ml were associated with higher risk for treatment failure in Head-and-Neck patients. Patients were repeatedly sampled in a longitudinal fashion at their Cmax plus trough levels and individual PK parameters were derived using a pop-PK approach. Preliminary results on 90 samples collected from the first 25 out of the 110 patients to be included have confirmed the marked inter-individual variability in Cetuximab exposure (i.e., &amp;gt;56% on trough levels and &amp;gt;55% on Cmax values). Mean Cetuximab trough level was 54 ± 30 µg/ml (range: 12-104 µg/ml) and mean Cmax value was 211 ± 116 µg/ml (range: 75-418 µg/ml), with several individuals (8 out of 25, i.e., 32%) showing plasma exposure below the expected trough levels associated with efficacy. Although preliminary, our data confirm that PK variability is massive with mAbs. This observation suggests that Therapeutic Drug Monitoring, using appropriate LC-MS/MS method, could help appraising interpatient variability at bedside and detecting individuals with exposure levels out of the range usually observed. Citation Format: Clemence Marin, Nihel Khoudour, Aurélien Millet, Dorothée Lebert, Pauline Bros, Fabienne Thomas, David Ternant, Jerôme Guitton, Mourad Hamimed, Benoit Blanchet, Sebastien Salas, Joseph Ciccolini. A multiplex LC-MS/MS method for assaying mAbs in oncology: Application to the CETUXIMAX GPCO-Unicancer trial on cetuximab pharmacokinetics in head and neck cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1144.

Does difference between label and actual potency of factor VIII concentrate affect pharmacokinetic-guided dosing of replacement therapy in haemophilia A?

BackgroundTo account for interindividual variability in the pharmacokinetics (PK) of factor concentrates, PK‐guided dosing is increasingly implemented in haemophilia patients. Calculations are based on provided label potency, but legislation allows a potency difference of ±20% between label and actual potency. It is unknown if these differences affect PK guidance.AimExplore the effects of potency differences on individual factor VIII (FVIII) PK parameters and the prediction of FVIII trough levels of dosing regimens.MethodsWe analyzed individual preoperative PK profiling data from severe and moderate haemophilia A patients included in the OPTI‐CLOT randomized controlled trial. Label and actual potency were compared, with data on potency provided by pharmaceutical companies. For both potencies, individual PK parameters were estimated and concentration‐time curves were constructed by nonlinear mixed‐effects modelling. Finally, we explored the effect of both the identified and the maximum legislated potency difference on predicted FVIII trough levels infused in a low and high dose regimen.ResultsIn 45/50 included patients, actual potency was higher than its label potency. The median potency difference was 6.0% (range ‐9.2% to 18.4%) and resulted in varying individual PK parameter estimates but practically identical FVIII concentration‐time curves. As expected, predicted FVIII trough levels were linearly correlated to the actual dose.ConclusionIt is not necessary to take potency differences into account when applying PK guidance of FVIII concentrates in haemophilia A patients. However, when the patient is switched to another FVIII batch after PK‐guided dosing, trough levels may deviate ±20% from calculations based on label dose.

Proposal for individualized dosing of eculizumab in atypical haemolytic uraemic syndrome: patient friendly and cost-effective.

Eculizumab is a lifesaving yet expensive drug for atypical haemolytic uraemic syndrome (aHUS). Current guidelines advise a fixed-dosing schedule, which can be suboptimal and inflexible in the individual patient. We evaluated the pharmacokinetics (PK) and pharmacodynamics (PD) [classical pathway (CP) activity levels] of eculizumab in 48 patients, consisting of 849 time-concentration data and 569 CP activity levels. PK-PD modelling was performed with non-linear mixed-effects modelling. The final model was used to develop improved dosing strategies. A PK model with parallel linear and non-linear elimination rates best described the data with the parameter estimates clearance 0.163 L/day, volume of distribution 6.42 L, maximal rate 29.6 mg/day and concentration for 50% of maximum rate 37.9 mg/L. The PK-PD relation between eculizumab concentration and CP activity was described using an inhibitory Emax model with the parameter estimates baseline 101%, maximal inhibitory effect 95.9%, concentration for 50% inhibition 22.0 mg/L and Hillcoefficient5.42. A weight-based loading dose, followed by PK-guided dosing was found to improve treatment. On day 7, we predict 99.95% of the patients to reach the efficacy target (CP activity<10%),compared with 94.75% with standard dosing. Comparable efficacy was predicted during the maintenance phase, while the dosing interval could be prolonged in ∼33% of the population by means of individualized dosing. With a fixed-dose 4-week dosing interval to allow for holidays, treatment costs will increase by 7.1% and we predict 91% of the patients will reach the efficacy target. A patient-friendly individualized dosing strategy of eculizumab has the potential to improve treatment response at reduced costs.

Is pharmacokinetic-guided dosing of desmopressin and von Willebrand factor-containing concentrates in individuals with von Willebrand disease or low von Willebrand factor reliable and feasible? A protocol for a multicentre, non-randomised, open label cohort trial, the OPTI-CLOT: to WiN study

IntroductionVon Willebrand disease (VWD) is a bleeding disorder, caused by a deficiency or defect of von Willebrand factor (VWF). In case of medical procedures or bleeding, patients are treated with...

Design of a Prospective Study on Pharmacokinetic-Guided Dosing of Prophylactic Factor Replacement in Hemophilia A and B (OPTI-CLOT TARGET Study).

In resource-rich countries, almost all severe hemophilia patients receive prophylactic replacement therapy with factor concentrates to prevent spontaneous bleeding in joints and muscles to decrease the development of arthropathy and risk of long-term disability. Pharmacokinetic (PK)-guided dosing can be applied to individualize factor replacement therapy, as interindividual differences in PK parameters influence factor VIII (FVIII) and FIX activity levels. PK-guided dosing may therefore lead to more optimal safeguarding of FVIII/FIX levels during prophylaxis and on demand treatment. The OPTI-CLOT TARGET study is a multicenter, nonrandomized, prospective cohort study that aims to investigate the reliability and feasibility of PK-guided prophylactic dosing of factor concentrates in hemophilia-A and -B patients in daily clinical practice. At least 50 patients of all ages on prophylactic treatment using standard half-life (SHL) and extended half-life (EHL) factor concentrates will be included during 9 months and will receive PK-guided treatment. As primary endpoint, a minimum of four FVIII/FIX levels will be compared with FVIII/FIX levels as predicted by Bayesian forecasting. Secondary endpoints are the association of FVIII and FIX levels with bleeding episodes and physical activity, expectations and experiences, economic analyses, and optimization of population PK models. This study will lead to more insight in the reliability and feasibility of PK-guided dosing in hemophilia patients. Moreover, it will contribute to personalization of treatment by greater knowledge of dosing regimens needed to prevent and treat bleeding in the individual patient and provide evidence to more clearly associate factor activity levels with bleeding risk.