Difference In pK Research Articles

Population modeling analyses of crizotinib in pediatric patients with ALK-positive advanced cancers.

Alterations in the ALK (anaplastic lymphoma kinase) gene play a critical role in pathogenesis of anaplastic large cell lymphoma (ALCL). Crizotinib is a small molecule competitive inhibitor of ALK, ROS1, and MET kinases and was approved for pediatric patients with ALK-positive relapsed or refractory, systemic ALCL, and ALK-positive unresectable, recurrent, or refractory inflammatory myofibroblastic tumors (IMT). Crizotinib data from pediatric patients with relapsed or refractory solid tumors, IMT, or ALCL were included in the analyses. All patients received crizotinib orally at doses ranging from 100 to 365mg/m2 twice daily (BID). PopPK analyses were conducted to characterize crizotinib disposition in pediatric patients. Exposure-response (ER) safety and antitumor analyses were conducted to characterize relationships between crizotinib dose or exposure with safety and antitumor activity endpoints of interest. The population pharmacokinetic (popPK), ER safety, and ER antitumor analysis included 98, 110, and 36 pediatric patients, respectively. A one-compartment pharmacokinetic model with allometric scaling, first-order elimination, and first-order absorption with lag time adequately described the data. Natural log-transformed model-predicted crizotinib AUCss (steady-state area under the concentration-time curve) demonstrated a significant, positive relationship with Grade ≥3 NEUTROPENIA and Any Grade VISION DISORDER. Crizotinib dose demonstrated a positive relationship with objective response rate. No significant differences in PK were identified across a wide range of ages or across tumor types, suggesting body surface area (BSA)-based dosing adequately adjusted for differences in patient size to achieve similar systemic crizotinib exposures across young children and adolescent pediatric patients. None of the myelosuppressive events except Grade ≥3 NEUTROPENIA had significant relationships identified with crizotinib dose or exposure, suggesting crizotinib is a tolerable treatment with less hematological toxicity than traditional chemotherapy regimens for pediatric patients with ALK-mutated cancers. Results from the presented analyses support the pediatric dosing recommendations in the product label.

OriCAR-017, a novel GPRC5D-targeting CAR-T, in patients with relapsed/refractory multiple myeloma: Long term follow-up results of phase 1 study (POLARIS).

7511 Background: OriCAR-017 is a novel GPRC5D-targeting CAR T-cells. Previously we had presented early study results (Lancet Haematol 2023: 10: e107–16) following OriCAR-017 treatment, the results of good durable response and long-term safety profile support OriCAR-017 is highly probable to be developed as a promising therapy for patients with relapsed or refractory multiple myeloma. All patients had completed at least 2-year follow-up per protocol. Methods: Ten median age of 64 years (range 41–71) pretreated RRMM pts with a median of 5.5 prior lines therapies (range 3-17) received OriCAR-017. Seven (70.0%) pts were cytogenetics high risk, 4 (40.0%) pts had EMD, 3 (30.0%) pts had ISS stage(III), 2 (20.0%) pts had received prior anti-CD38 and 2 (20.0%) pts were treated with auto-HSCT and 5 (50.0%) pts were treated with BCMA CAR-T. Patients were administrated in a single dose of intravenous OriCAR-017 at 1×10⁶CAR-T/kg (DL1,n=3), 3×10⁶CAR-T/kg(DL2,n=4), or 6×10⁶CAR-T/kg(DL3,n=3). Results: At data cut-off (Jan 16, 2024), all 10 enrolled pts had been evaluated for response with the last patient completed 24 months follow up. ORR was 100.0%, sCR was 80.0%, VGPR was 20.0%. All patients achieved MRD negativity at day 28. The mDOR was 10.43 months (95%CI, 5.00-17.00); mPFS was 11.37 months (95%CI, 5.93-18.00) while mOS has not reached (7 pts still undergo survival follow-up, 1 pt died from disease progress, 2 from COVID). The mDOR was 17.23 months (95%CI, 7.33-NR) and the mPFS was 19.10 months (95%CI, 8.30-NR) with 67% prior BCMA CAR-T pts at high dose level. Nine (90%) pts had grade 1 CRS, and 1 (10%) pt had grade 2 CRS. No ≥ G3 CRS was observed. Median time to CRS onset was 2 days (range 1–9) and median duration was 6 days (range 3–9). No ICANS, nor DLTs were observed. There were no SAE and no treatment-related deaths. No PK difference across dose levels with Cmax 7354.7 copies/μL and AUC0-28 68587 copies·day/μg. At high doses, CAR-T cells were detectable at 9 months and one responder at 21 months above the LLOQ. The patients with Tlast≧9 months had a longer PFS than those with Tlast <9 months. No correlation of antigen expression and efficacy was observed. All patients had the positive GPRC5D expression in bone marrow CD138+MMPC at baseline, compared with 50% of relapsed pts had a reduced expression measured by flow cytometry. Conclusions: The updated results showed OriCAR-017 continued to provide deep and durable responses, MRD negativity was achieved in all RRMM pts, including in pts refractory to anti-CD38, PIs and IMIDs and failure to BCMA-directed therapy with excellent safety profile. The results of long-term efficacy and safety follow up support that OriCAR-017 is highly probable to be developed as a promising therapy in RRMM. Further clinical development efforts are undertaking to confirm the clinical benefits of OriCAR-017. Clinical trial information: NCT05016778 .

Abstract 7173: Animal pharmacokinetics of an anti-Her2+ immunoliposome of docetaxel

Abstract Despite the success of docetaxel in combination with trastuzumab in HER2+ breast cancer, docetaxel still has serious limitations, including poor water solubility and the canonical systemic toxicity of taxanes. These side effects of taxanes need to be overcome to improve patient management. In this context, we have developed a nanoparticle drug delivery system. We have developed an immunoliposome loaded with docetaxel and grafted with trastuzumab using a microfluidic method by mixing an aqueous phase (KH2PO4 buffer) and an organic phase composed of phosphatidylcholine, cholesterol and PEGmal in a molar ratio of 50:31:1, to which docetaxel is added at a rate of 1.8% of the total lipid. We perform a thiolation reaction to graft the trastuzumab onto the polyethylene glycol chain. Resulting immunoliposomes were characterized by a mean diameter of 140 nm, a docetaxel encapsulation rate of 73% and a trastuzumab uptake rate of 400 units of trastuzumab by nanoparticle. C57BL/6 mice were administered with docetaxel 1.9 mg/kg and trastuzumab 160 ng/kg or a mixture of free drugs or as liposomes at the same dose by intraperitoneal injection. Blood was collected 1h, 2h, 3h, 6h, 8h and 24h after injection and plasma was analyzed by HPLC-UV with Paclitaxel as internal standard. For each treatment group, pharmacokinetic parameters and exposure metrics were calculated using PKanalix®: half-life T1/2, elimination rate constant Kel and area under the curve AUC at the end points (AUCtlast) and infinity (AUCinfinity). Statistical tests were performed with Sigmastats®. The results showed a marked change in pharmacokinetics with increased plasma exposure with liposomal docetaxel. Preliminary results show a longer half-life for liposomal docetaxel (40.76 h VS. 4.33 h, i.e., a 9.4-fold increase). The concentration of docetaxel appeared to decrease more rapidly between T1h and T6h with free docetaxel (Kel 0.16h-1) than with liposomal docetaxel (Kel 0.017h-1). The concentration of docetaxel reached a plateau over time, up to 24 hours (52.72± 9.45 ng/ml) in mice treated with immunoliposomes whereas Docetaxel was undetectable at T24h when treated with free drugs. There was a statistical difference in PK at T6h between liposomal docetaxel and free docetaxel, 69.86 ± 15.25 ng/ml and 53.67 ± 4.92 ng/ml, respectively (p < 0.001, non-paired t-test). Liposomal docetaxel showed higher AUC0-t (x3.75) and AUC0-∞ values (x5.9) compared to non-liposomal docetaxel. In conclusion, these preliminary results suggest that we have developed a promising immunoliposome for the systemic delivery of docetaxel in HER2+ breast cancer with sustained exposure. Citation Format: Mathilde Dacos, Erwan Diroff, Sarah Giacometti, Joseph Ciccolini, Raphaelle Fanciullino. Animal pharmacokinetics of an anti-Her2+ immunoliposome of docetaxel [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7173.

Gender Differences in Pharmacokinetics: A Perspective on Contrast Agents.

Gender is an important risk factor for adverse drug reactions. Women report significantly more adverse drug reactions than men. There is a growing consensus that gender differences in drug PK is a main contributor to higher drug toxicity in women. These differences stem from physiological differences (body composition, plasma protein concentrations, and liver and kidney function), drug interactions, and comorbidities. Contrast agents are widely used to enhance diagnostic performance in computed tomography and magnetic resonance imaging. Despite their broad use, these contrast agents can lead to important adverse reactions including hypersensitivity reactions, nephropathy, and hyperthyroidism. Importantly, female gender is one of the main risk factors for contrast agent toxicity. As these adverse reactions may be related to gender differences in PK, this perspective aims to describe distribution and elimination pathways of commonly used contrast agents and to critically discuss gender differences in these processes.

769-P: Effect of Food on the Pharmacokinetics, Safety, and Tolerability of Orforglipron (LY3502970), an Oral, Nonpeptide GLP-1 Receptor Agonist

Orforglipron [OFG (LY3502970)] is an oral, non-peptide glucagon-like peptide-1 receptor agonist (GLP-1 RA). This reports the results of 2 studies that assessed PK, safety, and tolerability of OFG in healthy subjects, fasted and fed state, after single and repeated doses. Studies A and B were phase 1, randomized, open-label, crossover studies evaluating the effect of food on OFG concentration in healthy adults after a single 3 mg dose (study A) and after a 16 mg daily dose (study B), which was reached by weekly dose escalation starting with 2 mg. Based on statistical analysis, Cmax was 23% (study A) and 21% (study B) lower in the fed state. AUC(0-∞), and AUC(0-24) were 24% (study A) and 18% (study B) lower when administered with food. Tmax and T1/2 were similar with or without food. In study A and B, treatment emergent adverse events (TEAEs) were mild. In study B, TEAEs occurred most often with the starting dose and decreased with dose escalation. The most common TEAEs in study B were decreased appetite (69.7%), nausea (48.5%), and vomiting (45.5%). Overall mean exposure to OFG based on Cmax and AUC was numerically lower when administered with food and had little effect on Tmax and T1/2. Based on exposure response relationship, PK differences are unlikely to result in clinically meaningful differences in OFG safety and efficacy. Phase 3 studies are planned without food or water restrictions. Disclosure X.Ma: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. R.Liu: None. E.J.Pratt: Employee; Eli Lilly and Company. C.Benson: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. S.N.Bhattachar: None.

A phase Ib study of porustobart (HBM4003), an anti-CTLA-4 heavy chain only monoclonal antibody, in combination with toripalimab in patients with hepatocellular carcinoma.

e16106 Background: Porustobart (HBM4003) is a fully human heavy chain only monoclonal antibody (HCAb) targeting CTLA-4. In addition to blocking the CTLA-4 pathway, it has been shown to effectively deplete intratumoral Treg cells in patients due to its engineered enhanced antibody-dependent cellular cytotoxicity (ADCC). Toripalimab is a recombinant, humanized anti-PD-1 monoclonal antibody. Here we reported the results of a phase Ib study that evaluated porustobart plus toripalimab in patients with hepatocellular carcinoma (HCC). Methods: This is a phase Ib dose expansion study (NCT05149027). Patients with advanced HCC (n=28) received porustobart 0.45 mg/kg plus toripalimab 240 mg every three weeks (Q3W) in both Cohort 1 and Cohort 2. Cohort 1 recruited pts who failed previous anti-VEGFR multikinase inhibitor(s) treatment while have not received anti-PD-(L)1 treatment (n=16); Cohort 2 recruited patients who failed previous anti-PD-(L)1 and anti-VEGF(R) treatments (n=12). The primary endpoint was ORR per RECIST 1.1. Results: As of 9 Dec 2022, median follow-up time was 3.6 months (range: 1-7 months). In Cohort 1, ORR and DCR were 46.7% (95%CI: 21.3-73.4) and 73.3% (95%CI: 44.9-92.2) respectively in 15 patients with post-treatment tumor assessments. In Cohort 2, the ORR and DCR were 9.1% (95%CI: 0.2-41.3) and 54.5% (95%CI: 23.4-83.3) respectively in 11 patients with post-treatment tumor assessments. PFS or OS data were not mature by the cut-off date. Treatment-related adverse events (TRAEs) were reported in 89.3% (25/28) patients, and Grade 3 TRAEs were reported in 39.3% (11/28) patients. The most common (≥20%) TRAEs with all grades by pooled term were liver function test abnormal 46.4% (13/28), thrombocytopenia 42.9% (12/28), pyrexia 32.1% (9/28), asthenia 28.6% (8/28), anemia 25% (7/28), decreased appetite 25% (7/28), blood bilirubin increased 21.4% (6/28), leucopenia 21.4% (6/28), lymphopenia 21.4% (6/28), nausea 21.4% (6/28) and neutropenia 21.4% (6/28). TRAEs leading to permanent discontinuation of porustobart were reported in 3 (10.7%) patients. No Grade 4 or Grade 5 TRAE was reported. Porustobart promoted the clearance of Treg cells and the proliferation of CD4+ T cells and CD8+ T cells in peripheral blood that attested to its MOA. Greater effects were observed in Cohort 1. Taken together with the clinical observations these results suggested that PD-(L)1 inhibitor naïve patients have a larger available pool of effectors to induce anti-tumor activity in the presence of effective Treg depletion. No noticeable differences in PK between Cohort 1 and Cohort 2 were observed. Conclusions: Porustobart 0.45 mg/kg in combination with toripalimab 240mg Q3W showed promising anti-tumor activity in patients with advanced HCC, as well as an acceptable safety profile. Clinical trial information: NCT05149027 .

Protein Matrix Impacts Essential Amino Acid Response To Feeding

It is well established that muscle protein turnover is highly response to increases in plasma essential amino acids (EAA). Digestion and amino acid absorption kinetics appear to strongly modulate post-prandial muscle protein synthesis. Despite this relationship, little is known about the effects of the protein matrix on plasma EAA appearance. PURPOSE: To assess if protein matrix alters plasma EAA pharmacokinetics (PK). METHODS: 24 healthy young individuals (24.7 ± 4.7y; BMI = 24.6 ± 3.2 kg/m2) completed this study. Participants consumed one of the following protein matrices: whey protein isolate (W; 6.8 g of EAA), beef sirloin (B; 7.0 g of EAA), or free form EAA enriched W (FW; 5.6 g of EAA). Blood samples were collected before and four hours following the ingestion of W, B, and FW. Plasma EAA were analyzed via LC-MS/MS. Standard pK values were calculated: area under the curve above baseline (AUCi), max EAA concentration (Cmax), EAA concentration change from baseline to EAACmax (ΔEAA), rate to Cmax, and time to Cmax. To examine group differences in EAA pK a one-way analysis of variance with Tukey post hoc test was performed with significance accepted at P ≤ 0.05. RESULTS: Significant group differences were noted for all measured pK (p ≤ 0.005). Post hoc comparisons indicated AUCi was significantly lower in W (50705.6 ± 13483.3 μmol/L/min) as compared to FW (84793.8 ± 15989.7 μmol/L/min; p = 0.004) and B (77084.6 ± 25076.0 μmol/L/min; p = 0.028). Cmax, ΔEAA, and rate to Cmax was significantly higher in FW (Cmax = 1,920 ± 242.6 μmol/L; ΔEAA = 1012.4 ± 200.8 μmol/L; rate to Cmax = 30.1 ± 13.0 μmol/L/min) as compared to W (Cmax = 1343.1 ± 144.4 μmol/L, p ≤ 0.001; ΔEAA = 556.9 ± 160.1 μmol/L, p ≤ 0.001; rate to Cmax = 13.6 ± 7.6 μmol/L/min, p = 0.003) and B (Cmax = 1339.9 ± 213.5 μmol/L, p ≤ 0.001; ΔEAA = 543.8 ± 164.2 μmol/L, p ≤ 0.001; rate to Cmax = 4.9 ± 2.7 μmol/L/min, p ≤ 0.001). Lastly, the time to Cmax was slowest in B (135.0 ± 62.1 mins) as compared to W (47.5 ± 14.9 mins; p ≤ 0.001) and FW (36.3 ± 7.4 mins; p ≤ 0.001). CONCLUSION: Despite similar EAA content, pharmacokinetics were significantly different between treatments. Despite the lowest EAA content, FW resulted in the greatest plasma EAA availability and quickest time to peak. These results indicate that protein/amino acid digestion is a primary determinant of plasma EAA availability.

A reduced complexity cross between BALB/c substrains identifies Zhx2 as a candidate gene underlying oxycodone metabolite brain concentration and state‐dependent learning of opioid reward

Understanding the pharmacokinetic profile of an opioid drug is vital to therapeutic success, and mutations in human PK genes can drastically alter therapeutic efficacy of opioids. We observed that at 30 min post‐oxycodone administration (1.25 mg/kg, i.p.) BALB/cJ mice showed a higher whole brain concentration of oxycodone, and female specific increase in noroxycodone, and oxymorphone compared to BALB/cByJ. This observation could explain the sex‐specific increase in oxycodone state‐dependent conditioned place preference in BALB/cJ female mice. To potentially link behavioral differences with PK differences, we conducted quantitative trait locus (QTL) mapping of whole brain oxycodone and metabolite concentrations in a reduced complexity cross (RCC). Because BALB/cJ and BALB/cByJ substrains differ by ~8,500 SNPs/indels, large genetic loci identified in an F2 cross are offset by a dramatic reduction in potentially causal variants. QTL mapping in 133 BALB/cJ x BALB/cByJ F2 mice (68F, 65M) revealed a single QTL on chromosome 15 associated with brain oxymorphone concentration that explained 29% of the phenotypic variance in females. Oxymorphone is a full agonist at the mu opioid receptor, with 8x the potency of oxycodone, and likely contributes to oxycodone addictive properties. Hippocampal and striatal cis‐eQTL analysis revealed genetically regulated expression of Zhx2, a transcriptional inhibitor known to harbor a private BALB/cJ retroviral insertion that dramatically reduces protein expression and leads to sex specific dysregulation of CYP450 genes within the liver. Whole brain mass spectroscopy proteomics in the parental strains corroborated these eQTL findings. We hypothesize that decreased Zhx2 expression leads to increased CYP450 expression, increased brain oxymorphone, and increased oxycodone‐induced behaviors. Interestingly, human GWAS of nicotine consumption identified a nominal association (10^‐7) with ZHX2, indicating that this transcriptional repressor could influence metabolism of multiple drugs of abuse.

Population pharmacokinetics of rucaparib in patients with advanced ovarian cancer or other solid tumors.

To develop a population pharmacokinetics (PPK) model for rucaparib, an oral poly(ADP-ribose) polymerase inhibitor. The PPK analysis used PK data from patients in Study 1014 (NCT01009190, n = 35), Study 10 (NCT01482715, n = 123), and ARIEL2 (NCT01891344, n = 300), including intensive intravenous data (12-40mg), intensive and sparse oral data (12-360mg single-dose, 40-500mg once daily, and 240-840mg twice daily [BID]), and intensive single-dose oral data under fasted conditions and after a high-fat meal (40, 300, and 600mg). Rucaparib PK was well described by a two-compartment model with sequential zero-order release and first-order absorption and first-order elimination. A high-fat meal slightly increased bioavailability at 600mg but not at lower doses; this is not considered clinically significant, and rucaparib can be taken with or without food. Covariate effects of baseline creatinine clearance and albumin on rucaparib clearance were identified. Despite numerical increases in exposure with renal impairment, no dose adjustment is recommended for patients with mild or moderate renal impairment. No statistically significant relationships were detected for demographics, hepatic function (normal versus mild impairment), CYP1A2 and CYP2D6 phenotypes, or strong CYP1A2 or CYP2D6 inhibitors. Concomitant proton pump inhibitors showed no clinically significant effect on absorption. External validation of the model with data from ARIEL3 (NCT01968213) and TRITON2 (NCT02952534) studies showed no clinically meaningful PK differences across indications or sex. The PPK model adequately described rucaparib PK, and none of the covariates evaluated had a clinically relevant effect. GOV: Study 1014 (NCT01009190), Study 10 (NCT01482715), ARIEL2 (NCT01891344), ARIEL3 (NCT01968213), and TRITON2 (NCT02952534).

Interim Results from the First Clinical Study of CC-95251, an Anti-Signal Regulatory Protein-Alpha (SIRPα) Antibody, in Combination with Rituximab in Patients with Relapsed and/or Refractory Non-Hodgkin Lymphoma (R/R NHL)

Interim Results from the First Clinical Study of CC-95251, an Anti-Signal Regulatory Protein-Alpha (SIRPα) Antibody, in Combination with Rituximab in Patients with Relapsed and/or Refractory Non-Hodgkin Lymphoma (R/R NHL)

Human variability in polymorphic CYP2D6 metabolism: Implications for the risk assessment of chemicals in food and emerging designer drugs

The major human cytochrome P450 CYP2D6 isoform enzyme plays important roles in the liver and in the brain with regards to xenobiotic metabolism. Xenobiotics as CYP2D6 substrates include a whole range of pharmaceuticals, pesticides and plant alkaloids to cite but a few. In addition, a number of endogenous compounds have been shown to be substrates of CYP2D6 including trace amines in the brain such as tyramine and 5-methoxytryptamine as well as anandamide and progesterone. Because of the polymorphic nature of CYP2D6, considerable inter-phenotypic and inter-ethnic differences in the pharmaco/toxicokinetics (PK/TK) and metabolism of CYP2D6 substrates exist with potential consequences on the pharmacology and toxicity of chemicals. Here, large extensive literature searches have been performed to collect PK data from published human studies for a wide range of pharmaceutical probe substrates and investigate human variability in CYP2D6 metabolism. The computed kinetic parameters resulted in the largest open source database, quantifying inter-phenotypic differences for the kinetics of CYP2D6 probe substrates in Caucasian and Asian populations, to date. The database is available in supplementary material (CYPD6 DB) and EFSA knowledge junction (DOI to added). Subsequently, meta-analyses using a hierarchical Bayesian model for markers of chronic oral exposure (oral clearance, area under the plasma concentration time curve) and acute oral exposure (maximum plasma concentration (Cmax) provided estimates of inter-phenotypic differences and CYP2D6-related uncertainty factors (UFs) for chemical risk assessment in Caucasian and Asian populations classified as ultra-rapid (UM), extensive (EMs), intermediate (IMs) and poor metabolisers (PMs). The model allowed the integration of inter-individual (i.e. inter-phenotypic and inter-ethnic), inter-compound and inter-study variability together with uncertainty in each PK parameter. Key findings include 1. Higher frequencies of PMs in Caucasian populations compared to Asian populations (>8% vs 1-2%) for which EM and IM were the most frequent phenotype. 2. Large inter-phenotypic differences in PK parameters for Caucasian EMs (coefficients of variation (CV)>50%) compared with Caucasian PMs and Asian EMs and IMs (i.e CV<40%). 3. Inter-phenotypic PK differences between EMs and PMs in Caucasian populations increase with the quantitative contribution of CYP2D6 for the metabolism (fm) for a range of substrates (fmCYP2D6 range: 20-95% of dose) (range: 1-54) to a much larger extent than those for Asian populations (range: 1-4). 4. Exponential meta-regressions between FmCYP2D6 in EMs and inter-phenotypic differences were also shown to differ between Caucasian and Asian populations as well as CYP2D6-related UFs. Finally, implications of these results for the risk assessment of food chemicals and emerging designer drugs of public health concern, as CYP2D6 substrates, are highlighted and include the integration of in vitro metabolism data and CYP2D6-variability distributions for the development of quantitative in vitro in vivo extrapolation models.

No Time Dependence of Ciprofloxacin Pharmacokinetics in Critically Ill Adults: Comparison of Individual and Population Analyses

The aim of this prospective PK study was to evaluate the pharmacokinetics of ciprofloxacin dosed within the first 36 h (early phase) and after 3 days of treatment (delayed phase) using individual and population PK analysis. The secondary aim of the study was to evaluate possible dosing implications of the observed PK differences between early and delayed phases to achieve a PK/PD target for ciprofloxacin of AUC24/MIC ≥ 125. Blood concentrations of ciprofloxacin (1 and 4 h after dose and trough) were monitored in critically ill adults in the early and delayed phases of the treatment. Individual and population PK analyses were performed. Complete concentration-time profiles in the early phase, delayed phase, and both phases were obtained from 29, 15, and 14 patients, respectively. No systematic changes in ciprofloxacin PK parameters between the early and delayed phases were observed, although variability was higher at the early phase. Both individual and population analyses provided similar results. Simulations showed that after standard dosing, it is practically impossible to reach the recommended ciprofloxacin PK/PD target (AUC/MIC ≥ 125) for pathogens with MIC ≥ 0.5 mg/L. A dosing nomogram utilizing patients’ creatinine clearance and MIC values was constructed. Both individual and population analyses provided similar results. Therapeutic drug monitoring should be implemented to safeguard the optimal ciprofloxacin exposure.

Gender-based differences in brain and plasma pharmacokinetics of letrozole in sprague-dawley rats: Application of physiologically-based pharmacokinetic modeling to gain quantitative insights.

Based on the discovery that the estrogen synthase aromatase (CYP19A1) is abundantly expressed in high- grade gliomas, the aromatase inhibitor, letrozole is being investigated in pre-clinical models as a novel agent against this malignancy. Here, we investigated the systemic and brain pharmacokinetics of letrozole following single and steady state dosing in both male and female Sprague-Dawley rats. Furthermore, we employed physiologically-based pharmacokinetic (PBPK) modeling to gain quantitative insights into the blood-brain barrier penetration of this drug. Letrozole (4 mg/kg) was administered intraperitoneally daily for 5 days (for males) and 11 days (for females) and intracerebral microdialysis was performed for brain extracellular fluid (ECF) collection simultaneously with venous blood sampling. Drug levels were measured using HPLC and non-compartmental analysis was conducted employing WinNonlin®. Simcyp animal simulator was used for conducting bottom-up PBPK approach incorporating the specified multi-compartment brain model. Overall, marked gender-specific differences in the systemic and brain pharmacokinetics of letrozole were observed. Letrozole clearance was much slower in female rats resulting in markedly higher plasma and brain drug concentrations. At steady state, the plasma AUC 0–24 was 103.0 and 24.8 μg*h/ml and brain ECF AUC 0–12 was 24.0 and 4.8 μg*h/ml in female and male rats, respectively. The PBPK model simulated brain concentration profiles were in close agreement with the observed profiles. While gender-specific differences in letrozole PK are not observed in the clinical setting, these findings will guide the dose optimization during pre-clinical investigations of this compound. The PBPK model will serve as an important clinical translational tool.

Teicoplanin physiologically based pharmacokinetic modeling offers a quantitative assessment of a theoretical influence of serum albumin and renal function on its disposition

Variability in teicoplanin pharmacokinetics has been explained by multiple factors such as body weight, renal function, and serum albumin level. To improve mechanistic understanding of the causes of variability, a physiologically based pharmacokinetic (PBPK) model can be used as a systematic platform. In this study, a PBPK model of teicoplanin was developed to quantitatively assess the effects of physiological changes due to disease status using virtual populations. Predictive performance of the models was evaluated by comparing simulated and observed concentration-time profiles of teicoplanin. Subsequently, sensitivity analyses were conducted to identify potential factors contributing to individual differences in teicoplanin PK. The developed PBPK model generated concentration-time profiles that were comparable to clinical observations in healthy adults, including Caucasians and Japanese, and after single-dose and multiple-dose administration. The predicted PK parameters (i.e., Cmax, AUC, clearance) were within a two-fold range of the observed data in patients with renal impairments as well as healthy adults. Changes in total and unbound teicoplanin concentrations at 72 h, after various dosing regimens (tested 4-14 mg/kg q12h for three doses as a loading dose and then 4-14 mg/kg daily as a maintenance dose), were sensitive to renal function and serum albumin concentrations. The PBPK model of teicoplanin provides mechanistic insight into the factors altering its disposition and allows assessments of the theoretical and quantitative impact of individual changes in physiological parameters on its PK even when an actual assessment with adequate sample sizes of patients is challenging.

Recurrent or progressive pediatric brain tumors: population pharmacokinetics and exposure-response analysis of pomalidomide.

Pomalidomide, an immunomodulatory drug, was investigated for pediatric brain tumors. The objectives of this analysis were to characterize the PK of pomalidomide and to examine exposure-response relationship in pediatric patients with recurrent or progressive primary brain tumors. Nonlinear mixed effects modeling was employed in developing a population PK model of pomalidomide using a total of 343 concentrations from 70 patients. Logistic regression models were used for exposure-response analyses. The PK of pomalidomide was adequately described with a one compartment model with first-order absorption and elimination. Body surface area (BSA) was identified as a statistically significant covariate of apparent clearance and volume of distribution; however, the impact of BSA on exposure parameters was not deemed clinically relevant. Pomalidomide exposure was not associated with higher probabilities of treatment-emergent adverse events or pomalidomide dose interruptions during Cycle 1. Covariates such as BSA, weight, sex, age, and race had no significant effect on safety endpoints. The PK of pomalidomide in pediatric patients with brain tumors was generally consistent with that in adult patients with multiple myeloma after adjustment for BSA. This is the first study to characterize PK of pomalidomide in pediatric patients, which supports BSA-based dosing for pediatric patients. This is the first study to characterize PK of pomalidomide in pediatric patients, which supports BSA-based dosing for pediatric patients. There is no significant pomalidomide PK difference between adults and pediatrics. Pomalidomide exposure was not associated with higher probabilities of treatment-emergent adverse event or pomalidomide dose interruptions during Cycle 1.

Abstract PO-115: Co-modeling of calcipotriol and paclitaxel in blood and tumor of KrasG12D mouse model of pancreatic cancer after i.v bolus dose of a micellar co-formulation

Abstract Stroma-modulating agents in combination with chemotherapy have emerged as a potential treatment for pancreatic cancer, and we are developing a combination therapy of Calcipotriol (Cal) and paclitaxel (PTX). Cal, a stroma-modulating agent de- activates the cancer associated fibroblasts, shifting the tumor microenvironment into a dynamic milieu that aids PTX delivery. However, Cal causes hypercalcemia. To mitigate toxicity and further improve tumor accumulation, we developed a micellar co-formulation (M-Cal/PTX). A biodistribution study in tumor, liver and spleen of an orthotopic Kras mouse model showed that 24 h after a single IV bolus dose (0.5 mg/kg Cal, 5 mg/kg PTX), Cal from M-Cal/PTX (M-Cal) was measurable in the tumors and livers but not blood. In contrast, Cal was not measurable in these tissues 24 h after IV dose of non-formulated free Cal. Even though PTX could be measured in blood 24 h after a single dose in both formulated and non-formulated groups, it was only measurable in the tumors of mice administered M-Cal/PTX. To better understand the distribution kinetics of M-Cal/PTX, we co-modeled blood and tumor concentrations using Phoenix NLME. Our analysis showed PK differences of M-Cal in healthy versus tumor-bearing mice. The elimination half-life (t1/2) of M-Cal in diseased mice was &amp;gt;4X shorter than that in healthy ones (0.089 h vs 0.38 h), which corresponded with increased uptake into the peripheral tissues. The uptake rate into the spleen was the highest; however, M-Cal persisted in tumor and liver because of the slow eliminations from these tissues. Unsurprisingly, our model estimated that the blood AUC0-inf in diseased mice was 5X less than that in the healthy counterparts, resulting from the significantly shorter t1/2. A similar analysis of PTX from M-Cal/PTX showed that the elimination half-life was about 2X shorter in diseased mice when compared to their healthy counterparts (0.58 h vs 1.2 h). This corresponded with a modest blood AUC0-inf decrease in tumor-bearing mice. Of the tumor and two organs evaluated, our model estimated PTX liver uptake to be the highest, followed by the spleen and then tumor. Nonetheless, PTX could still be measured in all three sites 24 h after M-Cal/PTX injection. We conclude that 1) PK of Cal and PTX from M-Cal/PTX differ between diseased and healthy mice, with a faster elimination in the tumor-bearing mice. 2) Reduced Cal AUC0-inf in blood and its presence in tumors are expected to offer the potential merits of a reduced systemic toxicity and increased efficacy respectively, because Cal toxicity is directly related with the elevated systemic exposure that exacerbates off-target vitamin D receptor activation. Future studies will focus on proof-of-concept efficacy and toxicity studies to demonstrate the potential therapeutic merits of our combination formulation regimen in the orthotopic Kras mouse model of pancreatic cancer. Citation Format: Victor Lincha, Jun Zhao, Xiaoxia Wen, Lillian Duong, Chun Li, Diana Chow. Co-modeling of calcipotriol and paclitaxel in blood and tumor of KrasG12D mouse model of pancreatic cancer after i.v bolus dose of a micellar co-formulation [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr PO-115.

Influence of Different Populations on Pharmacokinetic Bioequivalence Results: Can We Extrapolate Bioequivalence Results from One Population to Another?

In order for a regulatory agency to use bioequivalence results from one population to another, two formulations assessed as bioequivalent under fasted and fed conditions in one population must be bioequivalent in a geographically/ethnically different population under both conditions. Unfortunately, bioequivalence studies between a generic and its reference product for one submission are conducted using only one geographical/ethnic population. As bioequivalence study results between two populations for the same generic and reference products are not available, the food effect for the same reference product between two populations was compared. This is based on the rationale that if two products are bioequivalent under both fasted and fed conditions in two populations, even if there are PK differences in the product exposures between these two populations, the test to reference ratio, as well as the food effect, will remain constant within each population. Food effect (fed/fasted ratio) was calculated using pharmacokinetic data from publicly available regulatory resources and compared between two geographical/ethnic populations using the same reference for each studied drug product. Meta-analyses were conducted. Statistically significant differences (P<0.05) were found in the food effect between two populations for nine out of the ten (90%) available studied products. Among these, an observed clinical difference was suggested in three out of nine (33%) products. These results suggest that bioequivalence results from one population may not always be representative of what may be found in another population.

How preclinical infection models help define antibiotic doses in the clinic

Appropriate dosing of antibiotics is key in the treatment of bacterial infections to ensure clinical efficacy while avoiding toxic drug concentrations and minimizing emergence of resistance. As collection of sufficient clinical evidence is difficult for specific patient populations, infection types and pathogens, market authorization, dosing strategies and recommendations often rely on data obtained from in vitro and animal experiments. The aim of this review is to provide an overview of commonly used preclinical infection models, including their strengths and limitations. In vitro, static and dynamic time-kill experiments are the most frequently used methods for assessing pharmacokinetic/pharmacodynamic (PK/PD) associations. Limitations of in vitro models include the inability to account for the effects of the immune system, and uncertainties in clinically relevant bacterial concentrations, growth conditions and the implications of emerging resistant bacterial populations during experiments. Animal experiments, most commonly murine lung and thigh infections models, are considered a necessary link between in vitro data and the clinical situation. However, there are differences in pathophysiology, immunology, and PK between species. Mathematical modeling in which preclinical data are integrated with human population PK can facilitate translation of preclinical data to the patient's clinical situation. Moreover, PK/PD modeling and simulations can help in the design of clinical trials aiming to establish optimal dosing regimens to improve patient outcomes.

Effect of the Most Relevant CYP3A4 and CYP3A5 Polymorphisms on the Pharmacokinetic Parameters of 10 CYP3A Substrates.

Several cytochrome P450 (CYP) CYP3A polymorphisms were associated with reduced enzyme function. We aimed to evaluate the influence of these alleles on the pharmacokinetic parameters (PK) of several CYP3A substrates. We included 251 healthy volunteers who received a single dose of ambrisentan, atorvastatin, imatinib, aripiprazole, fentanyl, amlodipine, donepezil, olanzapine, fesoterodine, or quetiapine. The volunteers were genotyped for CYP3A4 and CYP3A5 polymorphisms by qPCR. To compare the PK across studies, measurements were corrected by the mean of each parameter for every drug and were logarithmically transformed. Neither CYP3A phenotype nor individual CYP3A4 or CYP3A5 polymorphisms were significantly associated with differences in PK. However, regarding the substrates that are exclusively metabolized by CYP3A, we observed a higher normalized AUC (p = 0.099) and a tendency of lower normalized Cl (p = 0.069) in CYP3A4 mutated allele carriers what was associated with diminished drug metabolism capacity. CYP3A4 polymorphisms did not show a pronounced influence on PK of the analysed drugs. If so, their impact could be detectable in a very small percentage of subjects. Although there are few subjects carrying CYP3A4 double mutations, the effect in those might be relevant, especially due to the majority of subjects lacking the CYP3A5 enzyme. In heterozygous subjects, the consequence might be less noticeable due to the high inducible potential of the CYP3A4 enzyme.

Phospholipid Component Defines Pharmacokinetic and Pharmacodynamic Properties of Synthetic High-Density Lipoproteins.

Synthetic high-density lipoprotein (sHDL) nanoparticles composed of apolipoprotein A-I mimetic peptide and phospholipids have been shown to reduce atherosclerosis in animal models. Cholesterol is mobilized from atheroma macrophages by sHDL into the blood compartment and delivered to the liver for elimination. Historically, sHDL drug discovery efforts were focused on optimizing peptide sequences for interaction with cholesterol cellular transporters rather than understanding how both sHDL components, peptide and lipid, influence its pharmacokinetic and pharmacodynamic profiles. We designed two sets of sHDL having either identical phospholipid but variable peptide sequences with different plasma stability or identical peptide and phospholipids with variable fatty acid chain length and saturation. We found that sHDL prepared with proteolytically stable 22A-P peptide had 2-fold longer circulation half-time relative to the less stable 22A peptide. Yet, longer half-life did not translate into any improvement in cholesterol mobilization. In contrast, sHDL with variable phospholipid compositions showed significant differences in phospholipid PK, with distearoyl phosphatidylcholine-based sHDL demonstrating the longest half-life of 6.0 hours relative to 1.0 hour for palmitoyl-oleoyl phosphatidylcholine-based sHDL. This increase in half-life corresponded to an approx. 6.5-fold increase in the area under the curve for the mobilized cholesterol. Therefore, the phospholipid component in sHDL plays a major role in cholesterol mobilization in vivo and should not be overlooked in the design of future sHDL. SIGNIFICANCE STATEMENT: The phospholipid composition in sHDL plays a critical role in determining half-life and cholesterol mobilization in vivo.