Dose Adjustment Recommendations Research Articles

Role of therapeutic drug monitoring in the treatment of multi-drug resistant tuberculosis

Tuberculosis (TB) is a leading cause of mortality worldwide, and resistance to anti-tuberculosis drugs is a challenge to effective treatment. Multi-drug resistant TB (MDR-TB) can be difficult to treat, requiring long durations of therapy and the use of second line drugs, increasing a patient’s risk for toxicities and treatment failure. Given the challenges treating MDR-TB, clinicians can improve the likelihood of successful outcomes by utilizing therapeutic drug monitoring (TDM). TDM is a clinical technique that utilizes measured drug concentrations from the patient to adjust therapy, increasing likelihood of therapeutic drug concentrations while minimizing the risk of toxic drug concentrations. This review paper provides an overview of the TDM process, pharmacokinetic parameters for MDR-TB drugs, and recommendations for dose adjustments following TDM.

Prospective Pharmacokinetic Evaluation of Venetoclax (VEN) in AML Demonstrates Significant and Variable Drug Interactions with Azole Antifungals That Increase Ven Exposure, Reduce Clearance, and Necessitate Re-Evaluation of Dose Adjustments

Background: Venetoclax (VEN) in combination with hypomethylating agents (HMA) or low dose cytarabine (LDAC) is the standard of care for the treatment of newly diagnosed AML in pts aged ≥ 75 yrs. or unfit for intensive chemotherapy. While considered low-intensity, myelosuppression is universal, leading to increased rates of infection in the setting of neutropenia. Antifungal prophylaxis during induction has significantly lowered treatment-related mortality (TRM) attributed to invasive fungal infections (Cornely et al, 2007). Azole antifungals, the treatment of choice, pose significant drug-drug interactions through inhibition of CYP3A4 and p-glycoprotein (P-gp), both responsible for VEN metabolism and clearance. This interaction alters VEN pharmacokinetics (PK), increases its exposure, and therefore requires substantial dose adjustments (Agarwal et al, 2017). We previously showed that dose adjusted VEN plus HMA when used concomitantly with azoles retains efficacy, but still resulted in prolonged myelosuppression (Rausch et al, 2022). Little real-world PK data exists to confirm whether the recommended dose adjustments are appropriate or require further refinement. Methods: Pharmacokinetic analysis was conducted during the induction cycle of the phase II study of cladribine plus LDAC and VEN as previously described (Kadia et al, 2022). VEN was administered on days 1-21 during induction and was dose-adjusted to either 100 mg (later amended to 50 mg), 100 mg, or 400 mg daily when used with posaconazole (posa), voriconazole (vori), or caspofungin (caspo), respectively. Dose adjustments were based on package insert recommendations. Prior to amendment, VEN 100 mg was administered with posa based on previously published PK analysis suggesting a 75% dose reduction of VEN with concomitant posa (Agarwal et al, 2017). Steady state VEN PK analysis was conducted on day 8 and trough levels were collected on days 12 and 16 of cycle 1. Levels obtained with concomitant caspo served as a reference level, assuming no significant interaction between VEN and caspo. VEN levels were analyzed via an institutionally developed liquid chromatography coupled mass spectrometry (LCMS) assay and PK analysis was conducted via non-compartmental method using WinOnlin. Results: Forty patients, median age 68 (range, 61-78), were included for pharmacokinetic analysis. Average VEN AUC (area under the exposure) and Cmax (maximum observed plasma concentration) was higher with concomitant vori or posa than with caspo regardless of dose adjustments. Posa in combination with VEN 100 mg increased average AUC by 103% and Cmax by 63%. Vori with VEN 100 mg increased AUC and Cmax by 77% and 43%, respectively. Among the 3 groups, posa with VEN 50 mg resulted in a VEN AUC and Cmax most similar to that observed with caspo and VEN 400 mg. Concomitant posa delayed VEN clearance by 74% with VEN 50 mg and 79% with VEN 100 mg. As a result, the accumulation index observed with posa was 12.5 + 19.98 with VEN 100 mg, 9.2 + 17.5 with VEN 50 mg, and 3.7 + 1.92 with vori, compared to 1.7 + 0.5 with caspo. Although there was interpatient variability in VEN trough levels, we observed consistent intra-patient trough levels. In addition, significant correlation between VEN AUC and VEN trough levels (p = 1 x 10 -4, r 2 = 0.89) was observed. Conclusions: Despite dose adjustments, VEN AUC is significantly higher among pts receiving azole antifungals compared to those receiving caspo. Posa resulted in more potent inhibition of VEN clearance and greater accumulation compared to vori, despite both agents considered strong CYP3A4 inhibitors. This may be a result of the dual inhibitory effect of posa on both CYP3A4 and P-gp activity or more potent inhibition of CYP3A4. Based on PK evaluation, our data suggest VEN 50 mg with concomitant posa provides more similar drug exposure to VEN 400 mg and may be more appropriate than 70 mg or 100 mg in this setting. Given the high accumulation index observed with posa, PK analyses during cycle 2 are ongoing. While there is inter-patient variability in VEN PK, intra-patient trough levels are consistent, correlate well with VEN AUC, and could be used for therapeutic drug monitoring.

Real world practices of luspatercept at an academic medical center.

Introduction: Luspatercept is approved for patients with very low-to intermediate-risk myelodysplastic syndrome (MDS). Dosing is based on pre-dose hemoglobin levels and transfusion requirements. This study aims to evaluate if a site with a pharmacist prospectively reviewing luspatercept doses achieves dose optimization, compared to a site that does not have a pharmacist prospectively reviewing doses. Methods: We performed a retrospective chart review involving patients age ≥18 years or older with MDS at a major academic medical center main campus, which does not have a pharmacist prospectively review luspatercept doses, and a satellite campus infusion center, which has a pharmacist prospectively reviewing doses. Patients included received at least one dose of luspatercept between January 1, 2017 through August 31, 2022. The primary endpoint is the percentage of off-label luspatercept doses not consistent with prescribing information (PI) recommended dose adjustments. Results: The study included 17 patients. Of the 162 doses evaluated, 37 (23%) were off-label. Off-label dosing at the main campus was more common than at a satellite location (29.6% vs. 2.4%; p < 0.003). More patients achieved transfusion independence at the satellite compared to the main campus (83.3% vs. 27.3% p < 0.39). Conclusions: There was a higher percentage of off-label dosing at a center without a pharmacist's prospective review vs. a center with a pharmacist's prospective review. On-label dose optimization may lead to a higher percentage of patients achieving transfusion independence. Enhancements in the current ordering and review process can be improved with the involvement of a pharmacist's prospective involvement at both centers.

Efficacy analysis of a novel dose-adjusting regimen for prolonged delayed injection allergen- specific immunotherapy for allergic rhinitis

Objective: To investigate the efficacy and safety of a novel dose adjustment schedule based on subcutaneous immunotherapy (SCIT) after a 16 weeks delayed injection during the maintenance period. Methods: Sixty-eight patients with allergic rhinitis (AR) who received dust mite cluster SCIT and had interrupted treatment for more than 16 weeks during the maintenance period were recruited at Beijing TongRen Hospital, from July to September 2020. They were randomly divided into the novel schedule group (n=34) and the guideline recommended schedule group (n=34). In addition, 34 patients who received dust mite SCIT at the same period were selected as the continuous treatment group (n=34). When receiving treatment again after delayed injection, the novel schedule group was injected directly with the initial dose of maintenance period (10 000 SQ), and the guideline recommended schedule group started the dosage accumulation again from the lowest dose (10 SQ), while the continuous treatment group was injected according to the original schedule. Changes in the combined symptom and medication score (CSMS) from baseline after 3 years of SCIT were used as the primary efficacy evaluation index. Local and systemic adverse events were recorded to evaluate safety. SPSS 23.0 was used for statistical analysis. Results: At the end of 3 years, CSMS in all three groups decreased significantly from baseline, and there was no significant difference in the 3-year change value of CSMS from baseline between the novel schedule group and the guideline recommended schedule group (-1.0±0.3 vs -1.3±0.4, P=0.655). There was also no significant difference in the change of CSMS between the two dose-adjusted groups and the continuous treatment groups (-0.8±0.3 vs -1.3±0.3, P=0.156). No systemic adverse events occurred between the novel schedule group and the guideline recommended schedule group after restarting treatment, and there was no significant difference in frequency of adverse events (0.5% vs 0.5%, P=0.698). Conclusion: There is no significant difference in efficacy and safety between the novel dose adjustment schedule and the recommended dose adjustment schedule when SCIT interrupted injection for more than 16 weeks. Furthermore, SCIT discontinuation of injection for more than 16 weeks doesn't significantly impact on 3-year efficacy.

Direct Oral Anticoagulants for the Treatment of Venous Thromboembolism in Obesity.

Background: Direct oral anticoagulants (DOACs) are known to have similar efficacy with a decreased risk of bleeding when compared to warfarin for the treatment of venous thromboembolism (VTE). In patients with obesity, there are limited data regarding the safety and efficacy of DOACs. Despite concerns for both under- and over-dosing patients with extremes of body weight, there are no dose adjustment recommendations in the package inserts for any of the DOACs. Objective: To evaluate the safety and efficacy of DOACs versus warfarin for the treatment of VTE in patients with obesity. Methods: This single-center, retrospective cohort study included obese patients initiated on DOAC or warfarin therapy for VTE from January 2015 to January 2022. Patients with cancer, hypercoagulable disorders, end-stage kidney disease, or pregnancy were excluded. The primary endpoint was VTE recurrence. Secondary endpoints included major and minor bleeding. Results: A total of 120 patients met criteria for inclusion. Ninety-two received DOAC therapy and 28 received warfarin. The primary endpoint occurred in 4 patients in the DOAC group and 3 patients in the warfarin group (P = 0.35). Major bleeding occurred in 2 patients. Minor bleeding events occurred in 10 (8.33%) patients. Of those, 6 (6.5%) events occurred in patients receiving a DOAC and 4 (14.3%) events occurred in patients receiving warfarin (P = 0.28). Limitations of this study include the retrospective single-center study design. Conclusions: There was a comparable risk of bleeding and recurrent VTE between DOACs and warfarin in patients initiated on therapy for VTE.

Individualized Treatment Patterns for Patients with Narcolepsy Treated with Oxybate: A Clinical Practice Perspective.

Real-world data regarding divided nightly dosing of oxybate and individualized prescribing in patients with narcolepsy are limited. Study objectives were to understand oxybate prescribing practices, including optimizing dose regimens and adjusting dosing per occasional changes in patients' routines, and physician recommendations for representative patient scenarios. A cross-sectional, web- and audio-based survey of physicians treating ≥2 patients with narcolepsy, prescribed nightly oxybate (sodium oxybate) dosing for ≥6 months, was conducted. Physicians were surveyed on patients' usual oxybate dosing regimens, frequency of and reasons for oxybate dosing-related discussions, and preferred methods for and perceptions of adjusting oxybate dosing. Physicians provided dosing-related guidance for 4 representative scenarios. Participating physicians (N=25) were neurologists (52%), psychiatrists (44%), and neuropsychiatrists (4%). Individualized oxybate prescribing practices were reflected by the variability of physicians' reporting of the percentage of their patients being prescribed once-nightly, twice-nightly, and thrice-nightly dosing regimens. Most physicians (68%) reported discussing adjusting individualized treatment to accommodate occasional changes to patients' routines; the most common reasons were consuming contraindicated beverages (alcohol; 65%) and travel (59%). Adjusting total nightly dose (68%) and dose timing (68%) were preferred adjustment methods. Most physicians (88%) felt the ability to individualize oxybate dosing was important and had a positive impact on ability to provide care. For each representative scenario, physicians provided several dose-adjustment recommendations, and physician responses encouraged patient participation in treatment decision-making. Physicians provided guidance supportive of oxybate dose adjustments to accommodate occasional changes in patients' routines, and perceived individualized dosing as important in providing care.

Medication guide for dose adjustment and management of cardiotoxicity and lipid metabolic adverse events of oral antineoplastic therapy.

The management of cardiotoxicity concerning the use of oral antineoplastic agents (OAAs) is a challenge for healthcare professionals. Our objective was to create a comprehensive medication management guide with dose adjustment recommendations on OAAs concerning cardiotoxic and lipid metabolic adverse events (AEs) to assist healthcare professionals when prescribing OAAs. A review of the available information on all dose adjustments necessary to safely prescribe and dispense OAAs concerning cardiotoxicity was conducted. In January 2023, we identified all OAAs authorized by the European Medicines Agency (EMA). For each drug, the latest summary of product characteristics (SPC) approved by the EMA and the tertiary data source Lexicomp® were reviewed. Cardiotoxic AEs were recorded, namely, QT interval prolongation, decrease in left ventricular ejection fraction (LVEF), imbalances in blood pressure (hypertension and hypotension), alterations in heart rate (tachycardia and bradycardia), and thrombosis. Any available dose adjustment recommendations in case of an occurrence of these adverse events were collected. In all, 93 different OAAs had been approved by the EMA and were reviewed. Among them, 51.6% have recognized cardiotoxic AEs and 10.8% can cause alterations in lipid metabolism. A total of 27 (29.0%) OAAs had specific recommendations regarding QT prolongation; 88.9% were listed in the SPC and 59.3% in Lexicomp®. Eight OAAs (9.68%) have reported a decrease in LVEF, and four of these drugs, namely, encorafenib, lorlatinib, ripretinib, and sunitinib, have specific management recommendations. Almost half (49.5%) of currently approved OAAs can potentially alter blood pressure; 34 (36.6%) of them have been reported to cause hypertension and 12 (12.9%) are related to hypotension. Tachycardia and/or bradycardia are associated with 22.6% and 8.6% of the evaluated drugs, respectively. Regarding thrombosis, 30 (32.3%) of the drugs analyzed included the appearance of a thrombus as a possible AE. More than half of the OAAs can produce cardiotoxic effects, with the most frequent being blood pressure alteration and QT interval prolongation with a non-depreciable incidence of LV dysfunction or thrombosis. Before starting the treatment, it is necessary to stratify baseline cardiovascular risk, plan a surveillance schedule, and consider referral to cardio-oncology units.

Pharmacist ambulatory pain services for a chronic non‐cancer pain clinic: a descriptive study

AbstractBackgroundPatients presenting to specialist pain clinics are often prescribed complex and high‐risk analgesic regimens. In this setting, pharmacists can help identify at risk patients and provide valuable clinical input to improve patient outcomes.AimTo evaluate the role of a clinical pharmacist in improving the triage, assessment and management of patients presenting to ambulatory pain clinics.MethodThis descriptive study enrolled patients from two chronic noncancer pain clinics from July to December 2021. A new clinical pharmacist service was devised, which operated as telehealth one day per week. The pharmacist was responsible for accepting referrals, triaging based on clinic criteria and updating them with prescription risk factors, in line with SafeScript's traffic light system. Pharmacist clinical services included completion of medication histories, drug dose interventions and patient education. This project received departmental ethical approval from the Eastern Health Office of Research and Ethics prior to commencement (Approval No: QA21‐068).ResultsThe pharmacist assessed 253 patients and identified prescription risk factors for 68 patients; of which 11 (16%) had received opioids from ≥4 prescribers, 10 (15%) were issued a monitored prescription from ≥4 pharmacies, seven (10%) were on high‐risk drug combinations, 25 (37%) had an Oral Morphine Equivalent Daily Dose (OMEDD) of 50–100 mg, and 26 (38%) with OMEDD &gt;100 mg. The pharmacist completed 67 medication histories and provided 22 accepted drug intervention recommendations to clinic physicians, including seven recommendations for dose adjustments, six to cease a medicine and nine to start a new medicine.ConclusionThe pharmacist incorporated SafeScript in the clinics' triage processes and provided valuable clinical interventions complementing the care provided by the pain physicians and the allied health staff.

Response to the FDA Decision Regarding DPYD Testing Prior to Fluoropyrimidine Chemotherapy.

Fluoropyrimidine (FP) chemotherapy is associated with severe, life-threatening toxicities, particularly among patients who carry deleterious germline variants in the DPYD gene. Pretreatment DPYD testing is standard of care throughout most of Europe; however, it has not been recommended in clinical practice guidelines in the United States. Due to increased risk of severe toxicity, a Citizen's Petition asked the US Food and Drug Administration (FDA) to update language in FP drug labels to recommend DPYD testing as part of a boxed warning and recommend FP dose reduction in patients carrying deleterious germline variants. In response, the FDA updated the capecitabine package insert to inform patients about the toxicity risk and test availability and consider DPYD testing. However, the FDA did not include a testing recommendation or requirement, or a boxed warning. Additionally, the FDA did not recommend FP dose adjustment in DPYD variant carriers. This review provides a critical assessment of the DPYD-FP pharmacogenetic association using the FDA's previously published Pharmacogenetic Pyramid, demonstrating that the evidence is compelling for recommending DPYD testing prior to FP treatment. Additionally, the FDA's stated concerns about recommending DPYD testing and DPYD-guided FP dose adjustment are addressed and discussed in the context of the FDA's other genetic testing and dose adjustment recommendations. We call on the FDA to follow our European counterparts in recommending DPYD testing and genotype-based dose adjustment to ensure patients with cancer receive safe and effective FP chemotherapy.

Impact of Obesity on the Drug-Drug Interaction Between Dolutegravir and Rifampicin or Any Other Strong Inducers.

Obesity is increasingly prevalent among people with HIV. Obesity can impact drug pharmacokinetics and consequently the magnitude of drug-drug interactions (DDIs) and, thus, the related recommendations for dose adjustment. Virtual clinical DDI studies were conducted using physiologically based pharmacokinetic (PBPK) modeling to compare the magnitude of the DDI between dolutegravir and rifampicin in nonobese, obese, and morbidly obese individuals. Each DDI scenario included a cohort of virtual individuals (50% female) between 20 and 50 years of age. Drug models for dolutegravir and rifampicin were verified against clinical observed data. The verified models were used to simulate the concurrent administration of rifampicin (600 mg) at steady state with dolutegravir (50 mg) administered twice daily in normal-weight (BMI 18.5-30 kg/m2), obese (BMI 30-40 kg/m2), and morbidly obese (BMI 40-50 kg/m2) individuals. Rifampicin was predicted to decrease dolutegravir area under the curve (AUC) by 72% in obese and 77% in morbidly obese vs 68% in nonobese individuals; however, dolutegravir trough concentrations were reduced to a similar extent (83% and 85% vs 85%). Twice-daily dolutegravir with rifampicin resulted in trough concentrations always above the protein-adjusted 90% inhibitory concentration for all BMI groups and above the 300 ng/mL threshold in a similar proportion for all BMI groups. The combined effect of obesity and induction by rifampicin was predicted to further decrease dolutegravir exposure but not the minimal concentration at the end of the dosing interval. Thus, dolutegravir 50 mg twice daily with rifampicin can be used in individuals with a high BMI up to 50 kg/m2.

Development and Validation of Physiologically Based Pharmacokinetic Model of Levetiracetam to Predict Exposure and Dose Optimization in Pediatrics

Levetiracetam (Lev) is an antiepileptic drug that has been increasingly used in the epilepsy pediatric population in recent years, but its pharmacokinetic behavior in pediatric population needs to be characterized clearly. Clinical trials for the pediatric drug remain difficult to conduct due to ethical and practical factors. The purpose of this study was to use the physiologically based pharmacokinetic (PBPK) model to predict changes in plasma exposure of Lev in pediatric patients and to provide recommendations for dose adjustment. A PBPK model of Lev in adults was developed using PK-Sim® software and extrapolated to the entire age range of the pediatric population. The model was evaluated using clinical pharmacokinetic data. The results showed the good fit between predictions and observations of the adult and pediatric models. The recommended doses for neonates, infants and children are 0.78, 1.67 and 1.22 times that of adults, respectively. Moreover, at the same dose, plasma exposure in adolescents was similar to that of adults. The PBPK models of Lev for adults and pediatrics were successfully developed and validated to provide a reference for the rational administration of drugs in the pediatric population.

Prediction for Plasma Trough Concentration and Optimal Dosing of Imatinib under Multiple Clinical Situations Using Physiologically Based Pharmacokinetic Modeling.

(1) Purpose: This study aimed to develop a physiologically based pharmacokinetic (PBPK) model to predict the trough concentration (C trough) of imatinib (IMA) at steady state in patients and to explore the role of free concentration (f up), α1-acid glycoprotein (AGP) level, and organic cation transporter 1 (OCT1) activity/expression in clinical efficacy. (2) Methods: The population PBPK model was built using physicochemical and biochemical properties, metabolizing and transporting kinetics, tissue distribution, and human physiological parameters. (3) Results: The PBPK model successfully predicted the C trough of IMA administered alone in chronic phase (CP) and accelerated phase (AP) patients, the C trough of IMA co-administered with six modulators, and C trough in CP patients with hepatic impairment. Most of the ratios between predicted and observed data are within 0.70-1.30. Additionally, the recommendations for dosing adjustments for IMA have been given under multiple clinical uses. The sensitivity analysis showed that exploring the f up and AGP level had a significant influence on the plasma C trough of IMA. Meanwhile, the simulations also revealed that OCT1 activity and expression had a significant impact on the intracellular C trough of IMA. (4) Conclusion: The current PBPK model can accurately predict the IMA C trough and provide appropriate dosing adjustment recommendations in a variety of clinical situations.

Frequency and predictors of inappropriate medication dosages for cardiovascular disease prevention in chronic kidney disease patients: A retrospective cross-sectional study in a Malaysian primary care clinic

Patients with chronic kidney disease (CKD) are at increased risk of cardiovascular events. This study aimed to assess the frequency of inappropriate medication dosages (IMD) for cardiovascular disease prevention among patients with CKD and its predictors in an urban academic primary care clinic in Selangor, Malaysia. All patients who attended the clinic from April to June 2019 and fulfilled the inclusion criteria were included in this cross-sectional study, except for those with an estimated glomerular filtration rate (eGFR) of more than 90 ml/min, diagnosed with urinary tract infection, pregnant or were on dialysis for end stage renal disease. Their prescriptions on the electronic medical record (EMR) system were evaluated for appropriateness using the dose adjustment recommendations based on the 2018 Malaysian Clinical Practice Guidelines on management of CKD. A total of 362 medical records were included in this study. 16.6% (95% Confidence Interval [CI]: 12.9–20.8) or 60 out of 362 of the patient records analysed contained medications prescribed with inappropriate dosages. Patients with higher stages of CKD were associated with higher odds of IMD, namely CKD stage G3b (adjusted Odds Ratio [aOR] 10.41; 95% CI: 2.31–46.88) and CKD stage 4–5 (aOR 15.76; 95% CI: 3.22–77.28). Other predictors of IMD were diagnosis of diabetes mellitus (aOR 6.40; 95% CI: 2.15–19.01), number of prescribed medications of 5 or more (aOR 4.69; 95% CI: 1.55–14.20), and eGFR reduction of more than 25% over one year (aOR 2.82; 95% CI: 1.41–5.65). Within the limitations of this study, we conclude that the occurrence of IMD for CVD prevention was low in CKD patients in this primary care clinic. Medications with inappropriate dosages identified in this study include simvastatin, fenofibrate, hydrochlorothiazide, spironolactone, metformin, gliclazide, sitagliptin, dapagliflozin and empagliflozin. Clinicians should consider the predictors of inappropriate medication dosages listed above when prescribing to patients with CKD to reduce the risk of medications-related toxicities and adverse effects. Limitations of this study should be considered when interpreting the findings presented.

The Official Journal of ATTD Advanced Technologies &amp; Treatments for Diabetes Conference 22‐25 February 2023 I Berlin &amp; Online

The Official Journal of ATTD Advanced Technologies &amp; Treatments for Diabetes Conference 22‐25 February 2023 I Berlin &amp; Online

Blood, dose recommendation reports and phone calls: Experiences of a therapeutic drug monitoring advisory service for vancomycin.

Dose-prediction software is recommended to enable area under the curve over 24 h (AUC24 )-guided dosing of the antibiotic vancomycin. However, uncertainty remains about how best to implement software in the clinic. We describe the activity, over 18 months, of a consultative therapeutic drug monitoring Advisory Service (the Service) for vancomycin that used dose-prediction software alongside clinical expertise, identifying factors that influence attainment of therapeutic targets. Of the 408 vancomycin dose reports provided for 182 courses of therapy, most (57%) recommended a dose change. The majority (82.8%, 193/233) of recommended dose adjustments were accepted by treating teams. A dose report was not published for 125 courses of therapy, with reasons including patient in intensive care unit or service error. An estimated 26.6h of staff time was allocated to Service activities each month. Publication of a dose report facilitated attainment of therapeutic targets (P = .002). Software integration could improve Service outcomes, avoiding errors and reducing staff workload.

Population Pharmacokinetics in Hepatic and Renal Impairment and PBPK Drug-Drug Interaction Simulations of Asciminib, a Novel Tyrosine Kinase Inhibitor in Chronic Myeloid Leukemia in Chronic Phase

Introduction: Asciminib, a first-in-class BCR::ABL1 inhibitor that works by specifically targeting the ABL myristoyl pocket (STAMP), has been recently approved by the FDA for adult patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase (Ph+ CML-CP) treated with ≥2 prior tyrosine kinase inhibitors (TKIs), as well as adult patients with Ph+ CML-CP with the T315I mutation. The recommended asciminib doses for patients with Ph+ CML-CP without the T315I mutation are 40 mg twice daily (BID), which is the dose tested in the pivotal phase III study (ASCEMBL), and a more patient-centric dose of 80 mg once daily (QD). For patients with the T315I mutation, the approved dose of asciminib is 200 mg BID. All asciminib drug-drug interaction (DDI) and hepatic and renal impairment studies were conducted at single or multiple doses of 40 mg. Here, we aim to assess the clinical impact of hepatic and renal impairment and of DDIs on the pharmacokinetics (PK) of asciminib and provide recommendations for eventual necessary dose adjustments. Methods: Organ impairment effect was quantified using population pharmacokinetics (PopPK), while DDIs were predicted using physiologically-based pharmacokinetics (PBPK). A 2-compartment PopPK model with a delayed first-order absorption and first-order elimination was developed for asciminib (Li et al. Clin Pharmacokinet, 2022). The original analysis included pooled PK data from patients receiving asciminib at 10−200 mg BID (in the phase I dose-finding study, NCT02081378) or 40 mg BID (in the phase III study ASCEMBL, NCT03106779), and identified baseline absolute glomerular filtration rate (aGFR), nominal total daily dose, body weight and formulation as significant covariates affecting asciminib PK. The model has been further extended to describe patients with renal (based on aGFR) or hepatic (based on Child-Pugh class) impairment, using data from two phase I PK studies in patients with renal (NCT03605277) or hepatic (NCT02857868) impairment. A PBPK model was developed and validated for asciminib using SimCYP v19.1. A stepwise "middle out” approach was used leveraging in vitro, in silico and in vivo data. The PBPK model was validated using single and multiple dose PK at 20‒400 mg daily dose as well as clinical DDI and PK data in patients with organ impairment. Comprehensive DDI scenarios and PK in patients with hepatic and renal impairment, which had not been clinically tested, were simulated at the different recommended doses of asciminib (40 mg BID, 80 mg QD, 200 mg BID). Results: There was no significant impact of hepatic function on asciminib exposure; a non-significant trend to lower clearance was observed in patients with severe hepatic impairment. The PopPK derived steady-state exposures (measured as area under the curve [AUC]0-24h) for patients with severe hepatic impairment were almost identical for both dosing regimens (40 mg BID: 13,018 ng*h/mL, 80 mg QD: 13,020 ng*h/mL), and only marginally higher than those of patients with normal hepatic function (12,638 ng*h/mL and 12,646 ng*h/mL, respectively), well within the therapeutic window of asciminib. Renal function assessment showed that clearance was slightly decreased in patients with renal impairment, although this was not clinically relevant. For both 80 mg QD and 40 mg BID, the median predicted AUC0-24h and maximum plasma concentration (Cmax) for severe renal impairment were 60% and 40% higher, respectively, than those of a typical individual with normal renal function. However, this difference is not considered to be clinically relevant given the relatively flat exposure-safety relationship over a 5-fold difference in exposure. The PBPK model predicted no drug interaction that would significantly impact the PK of asciminib (as a victim) or of other substrates (as a perpetrator). Overall, asciminib exposure was weakly affected by interactions with inducers and inhibitors as a victim (Figure 1B) and was predicted to be a weak inhibitor of CYP3A4 and P-gp at all tested doses and a weak to moderate inhibitor of CYP2C9 as a perpetrator (Figure 1A). Conclusions: Hepatic or renal impairment does not have a clinically significant impact on the PK of asciminib. Hence, dose adaptations for patients with hepatic or renal impairment are not warranted. Overall, asciminib has a manageable DDI risk at all recommended doses. Sponsor: Novartis. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Clinical use of lenvatinib in patients with previous renal and/or hepatic impairment and radioiodine-refractory differentiated thyroid cancer.

Lenvatinib is one the most active drugs in radioiodine‐refractory differentiated thyroid cancer (RR‐DTC) such that it has become an important therapeutic tool in tumor control and survival. Renal and hepatic impairments are common comorbidities in cancer patients. Treating these patients is a challenge that requires careful consideration. As a first approach to patients with RR‐DTC and renal or hepatic impairment, Summary of Product Characteristics recommendations for lenvatinib use and dose adjustments should be strictly followed. Close clinical and blood monitoring is the gold standard approach to optimizing lenvatinib's use during the whole course of treatment.

Prediction for optimal dosage of pazopanib under various clinical situations using physiologically based pharmacokinetic modeling.

This study aimed to apply a physiologically based pharmacokinetic (PBPK) model to predict optimal dosing regimens of pazopanib (PAZ) for safe and effective administration when co-administered with CYP3A4 inhibitors, acid-reducing agents, food, and administered in patients with hepatic impairment. Here, we have successfully developed the population PBPK model and the predicted PK variables by this model matched well with the clinically observed data. Most ratios of prediction to observation were between 0.5 and 2.0. Suitable dosage modifications of PAZ have been identified using the PBPK simulations in various situations, i.e., 200 mg once daily (OD) or 100 mg twice daily (BID) when co-administered with the two CYP3A4 inhibitors, 200 mg BID when simultaneously administered with food or 800 mg OD when avoiding food uptake simultaneously. Additionally, the PBPK model also suggested that dosing does not need to be adjusted when co-administered with esomeprazole and administration in patients with wild hepatic impairment. Furthermore, the PBPK model also suggested that PAZ is not recommended to be administered in patients with severe hepatic impairment. In summary, the present PBPK model can determine the optimal dosing adjustment recommendations in multiple clinical uses, which cannot be achieved by only focusing on AUC linear change of PK.

Dose Adjustment of Concomitant Antiseizure Medications During Cenobamate Treatment: Expert Opinion Consensus Recommendations.

Our objective was to provide expert consensus recommendations to improve treatment tolerability through dose adjustments of concomitant antiseizure medications (ASMs) during addition of cenobamate to existing ASM therapy in adult patients with uncontrolled focal seizures. A panel of seven epileptologists experienced in the use of ASMs, including cenobamate, used a modified Delphi process to reach consensus. The panelists discussed tolerability issues with concomitant ASMs during cenobamate titration and practical strategies for dose adjustments that may prevent or mitigate adverse effects. The resulting recommendations consider concomitant ASM dose level and specify proactive (prior to report of an adverse effect) and reactive (in response to report of an adverse effect) dose adjustment suggestions based on concomitant ASM pharmacokinetic and pharmacodynamic interactions with cenobamate. Specific dose adjustment recommendations are provided. We recommend proactively lowering the dose of clobazam, phenytoin, and phenobarbital due to their known drug-drug interactions with cenobamate, and lacosamide due to a pharmacodynamic interaction with cenobamate, to prevent adverse effects during cenobamate titration. Reactive lowering of a concomitant ASM dose is sufficient for other ASMs at standard dosing owing to quick resolution of adverse effects. For carbamazepine and lamotrigine doses exceeding the upper end of standard dosing (e.g., carbamazepine, greater than 1200mg/day; lamotrigine, greater than 500mg/day), we encourage consideration of proactive dose reduction at cenobamate 200mg/day to prevent potential adverse effects. All dose reductions for adverse effects can be repeated every 2weeks as dictated by the adverse effects. At cenobamate 200mg/day, we recommend that patients be evaluated for marked improvement of seizures and further dose reductions be considered to reduce potentially unnecessary polypharmacy. The primary goal of the recommended dose reductions of concomitant ASMs is to prevent or resolve adverse effects, thereby allowing cenobamate to reach the optimal dose to achieve the maximal potential of improving seizure control.

Steering Away from Current Amoxicillin Dose Reductions in Hospitalized Patients with Impaired Kidney Function to Avoid Subtherapeutic Drug Exposure.

Current dose reductions recommended for amoxicillin in patients with impaired kidney function could lead to suboptimal treatments. In a prospective, observational study in hospitalized adults with varying kidney function treated with an IV or oral dose of amoxicillin, amoxicillin concentrations were measured in 1–2 samples on the second day of treatment. Pharmacometric modelling and simulations were performed to evaluate the probability of target attainment (PTA) for 40% of the time above MIC following standard (1000 mg q6h), reduced or increased IV dosing strategies. A total of 210 amoxicillin samples was collected from 155 patients with kidney function based on a CKD-EPI of between 12 and 165 mL/min/1.73 m2. Amoxicillin clearance could be well predicted with body weight and CKD-EPI. Recommended dose adjustments resulted in a clinically relevant reduction in the PTA for the nonspecies-related PK/PD breakpoint MIC of 8 mg/L (92%, 62% and 38% with a CKD-EPI of 10, 20 and 30 mL/min/1.73 m2, respectively, versus 100% for the standard dose). For MICs ≤ 2 mg/L, PTA > 90% was reached in these patients following both reduced and standard dose regimens. Our study showed that for amoxicillin, recommended dose reductions with impaired kidney function could lead to subtherapeutic amoxicillin concentrations in hospitalized patients, especially when targeting less susceptible pathogens.