Clinical toxicity of antibody drug conjugates: a meta-analysis of payloads.

Background Antibody drug conjugates (ADCs) utilize a monoclonal antibody to deliver a cytotoxic payload specifically to tumor cells, limiting exposure to healthy tissues. Major clinical toxicities of ADCs include hematologic, hepatic, neurologic, and ophthalmic events, which are often dose-limiting. These events may be off-target effects caused by premature release of payload in circulation. A meta-analysis was performed to summarize key clinical safety data for ADCs by payload, and data permitting, establish a dose-response model for toxicity incidence as a function of payload, dose/regimen, and cancer type. Methods A literature search was performed to identify and extract data from clinical ADC studies. Toxicity incidence and severity were collected by treatment arm for anemia, neutropenia, thrombocytopenia, leukopenia, hepatic toxicity, peripheral neuropathy, and ocular toxicity. Exploratory plots, descriptive summaries, and logistic regression modelling were used to explore Grade ≥ 3 (G3/4) toxicities and assess the impact of covariates, including cancer type and dose/regimen. Results The dataset contained 70 publications; quantitative analysis included 43 studies with G3/4 toxicity information reported for the endpoints above. G3/4 anemia, neutropenia and peripheral neuropathy were consistently reported for MMAE ADCs, thrombocytopenia and hepatic toxicity for DM1, and ocular toxicity for MMAF. Safety profiles of MMAE, DM1, and DM4 ADCs differed between solid and hematologic cancers. Conclusions Published ADC clinical data is limited by non-uniform reporting for toxicity and lack of dosing information, limiting the ability to develop quantitative models relating toxicity to exposure. However, the current analysis suggests that key G3/4 toxicities of ADCs in the clinic are likely off-target and related to payload.

Investigation of the impact of hepatic impairment on the pharmacokinetics of dacomitinib.

Dacomitinib (PF-00299804) is a small-molecule inhibitor of the tyrosine kinases human epidermal growth factor receptor-1 (HER1; epidermal growth factor receptor, EGFR), HER2, and HER4 currently being developed for the treatment of lung cancer with sensitizing mutations in EGFR or refractory to EGFR-directed treatment. Dacomitinib is largely metabolized by the liver through oxidative and conjugative metabolism; therefore, determination of the impact of varying degrees of hepatic impairment on the pharmacokinetics (PK) of dacomitinib was warranted to ensure patient safety. In this phase I, open-label, parallel-group study, a single dose of dacomitinib was administered to healthy volunteers and to subjects with mild or moderate liver dysfunction, as determined by Child-Pugh classification. The primary goal of this study was to evaluate the effects of mild and moderate hepatic impairment on the single-dose PK profile of dacomitinib, as well as to assess the safety and tolerability in these subjects. Plasma protein binding and impact of hepatic function on the PK of the active metabolite PF-05199265 was also investigated. Twenty-five male subjects received dacomitinib 30 mg, with 8 subjects in the healthy- and mild-impairment cohorts and 9 subjects in the moderate-impairment cohort. Compared with healthy volunteers, there was no significant change in dacomitinib exposure in subjects with mild or moderate liver dysfunction and no observed alteration in plasma protein binding. No serious treatment-related adverse events were reported in any group, and dacomitinib was well tolerated. A dose adjustment does not appear necessary when administering dacomitinib to patients with mild or moderate hepatic impairment.

Limited sampling strategy of partial area under the concentration-time curves to estimate midazolam systemic clearance for cytochrome P450 3A phenotyping.

OBJECTIVE: Intravenous (IV) midazolam is the preferred cytochrome P450 (CYP) 3A probe for phenotyping, with systemic clearance (CL) estimating hepatic CYP3A activity. A limited sampling strategy was conducted to determine whether partial area under the concentration-time curves (AUCs) could reliably estimate midazolam systemic CL during conditions of CYP3A baseline activity, inhibition, and induction/activation. METHODS: Midazolam plasma concentrations during CYP3A baseline (n = 93), inhibition (n = 40), and induction/activation (n = 33) were obtained from 7 studies in healthy adults. Noncompartmental analysis determined observed CL (CL(obs)) and partial AUCs. Linear regression equations were derived from partial AUCs to estimate CL (CL(pred)) during CYP3A baseline, inhibition, and induction/activation. Preestablished criterion for linear regression analysis was r(2) ≥ 0.9. CL(pred) was compared with CL(obs), and relative bias and precision were assessed using percent mean prediction error and percent mean absolute error. RESULTS: During CYP3A baseline and inhibition, all evaluated partial AUCs failed to meet criterion of r(2) ≥ 0.9 and/or percent mean absolute error <15%. During CYP3A induction/activation, equations derived from partial AUCs from 0 to 1 hour (AUC0-1), 0 to 2 hours (AUC0-2), and 0 to 4 hours (AUC0-4) were acceptable, with good precision and minimal bias. These equations provided the same conclusions regarding equivalency testing compared with intense sampling. CONCLUSIONS: During CYP3A induction/activation, but not baseline or inhibition, midazolam partial AUC0-1, AUC0-2, and AUC0-4 reliably estimated systemic CL and consequently hepatic CYP3A activity in healthy adults.

A Comprehensive Review of the Clinical Pharmacokinetics, Pharmacodynamics, and Drug Interactions of Nirmatrelvir/Ritonavir.

Nirmatrelvir is a potent and selective inhibitor of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease that is used as an oral antiviral coronavirus disease 2019 (COVID-19) treatment. To sustain unbound systemic trough concentrations above the antiviral in vitro 90% effective concentration value (EC90), nirmatrelvir is coadministered with 100 mg of ritonavir, a pharmacokinetic enhancer. Ritonavir inhibits nirmatrelvir's cytochrome P450 (CYP) 3A4-mediated metabolism which results in renal elimination becoming the primary route of nirmatrelvir elimination when dosed concomitantly. Nirmatrelvir exhibits absorption-limited nonlinear pharmacokinetics. When coadministered with ritonavir in patients with mild-to-moderate COVID-19, nirmatrelvir reaches a maximum concentration of 3.43 µg/mL (11.7× EC90) in approximately 3 h on day 5 of dosing, with a geometric mean day 5 trough concentration of 1.57 µg/mL (5.4× EC90). Drug interactions with nirmatrelvir/ritonavir (PAXLOVIDTM) are primarily attributed to ritonavir-mediated CYP3A4 inhibition, and to a lesser extent CYP2D6 and P-glycoprotein inhibition. Population pharmacokinetics and quantitative systems pharmacology modeling support twice daily dosing of 300 mg/100 mg nirmatrelvir/ritonavir for 5 days, with a reduced 150 mg/100 mg dose for patients with moderate renal impairment. Rapid clinical development of nirmatrelvir/ritonavir in response to the emerging COVID-19 pandemic was enabled by innovations in clinical pharmacology research, including an adaptive phase 1 trial design allowing direct to pivotal phase 3 development, fluorine nuclear magnetic resonance spectroscopy to delineate absorption, distribution, metabolism, and excretion profiles, and innovative applications of model-informed drug development to accelerate development.

First-line Avelumab plus Chemotherapy in Patients with Advanced Solid Tumors: Results from the Phase Ib/II JAVELIN Chemotherapy Medley Study.

PURPOSE: Chemotherapy can potentially enhance the activity of immune checkpoint inhibitors by promoting immune priming. The phase Ib/II JAVELIN Chemotherapy Medley trial (NCT03317496) evaluated first-line avelumab + concurrent chemotherapy in patients with advanced urothelial carcinoma or non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Avelumab 800 or 1,200 mg was administered continuously every 3 weeks with standard doses of cisplatin + gemcitabine in patients with urothelial carcinoma, or carboplatin + pemetrexed in patients with nonsquamous NSCLC. Dual primary endpoints were dose-limiting toxicity (DLT; phase Ib) and confirmed objective response (phase Ib/II). RESULTS: In phase Ib, urothelial carcinoma and NSCLC cohorts received avelumab 800 mg (n = 13 and n = 6, respectively) or 1,200 mg (n = 6 each) + chemotherapy. In evaluable patients with urothelial carcinoma treated with avelumab 800 or 1,200 mg + chemotherapy, DLT occurred in 1/12 (8.3%) and 1/6 (16.7%), respectively; no DLT occurred in the NSCLC cohort. In phase II, 35 additional patients with urothelial carcinoma received avelumab 1,200 mg + chemotherapy. Across all treated patients, safety profiles were similar irrespective of avelumab dose. Objective response rates (95% confidence internal) with avelumab 800 or 1,200 mg + chemotherapy, respectively, across phase Ib/II, were 53.8% (25.1-80.8) and 39.0% (24.2-55.5) in urothelial carcinoma, and 50.0% (11.8-88.2) and 33.3% (4.3-77.7) in NSCLC. CONCLUSIONS: Preliminary efficacy and safety findings with avelumab + chemotherapy in urothelial carcinoma and NSCLC were consistent with previous studies of similar combination regimens. Conclusions about clinical activity are limited by small patient numbers. SIGNIFICANCE: This phase Ib/II trial evaluated avelumab (immune checkpoint inhibitor) administered concurrently with standard first-line chemotherapy in patients with advanced urothelial carcinoma or advanced nonsquamous NSCLC without actionable mutations. Efficacy and safety appeared consistent with previous studies of similar combinations, although patient numbers were small.

The Importance of Assessing Drug Pharmacokinetics and Pharmacodynamics in the Obese Population During Drug Development.

Obesity remains a US national health crisis and a growing concern worldwide. Concerningly, individuals who are obese are at an increased risk for comorbid diseases that include, but are not limited to, hypertension, diabetes, cardiovascular disease, and cancer. Beyond the risk for developing these conditions, obesity may also impact the pharmacological activity of the therapies being used to treat them and other disease states. The pharmacokinetics (PK), pharmacodynamics (PD), safety, and efficacy of therapies, both currently marketed and under clinical development, may be directly impacted by the physiological alterations that occur secondary to the occurrence of chronic excess body weight. The increased prevalence of this disease should not be ignored. Both private and federal institutions involved in drug research and development should consider, as appropriate, a greater inclusion of individuals who are obese in clinical trials throughout the entirety of drug development, and leverage the available PK, PD, safety, and efficacy data to make more informed dosing recommendations.

Model-informed drug development supporting the approval of the avelumab flat-dose regimen in patients with advanced renal cell carcinoma.

Avelumab is an anti-PD-L1 monoclonal antibody approved as monotherapy for Merkel cell carcinoma (MCC) and urothelial carcinoma (UC), and in combination with axitinib for advanced renal cell carcinoma (aRCC). Although initially approved with weight-based dosing (10 mg/kg intravenously [IV] every 2 weeks [Q2W]), avelumab was subsequently approved for flat dosing (800 mg IV Q2W) based on population pharmacokinetic (PopPK), exposure-efficacy, and exposure-safety modeling in MCC and UC. Here, through modeling and simulation, we provide justification for a flat-dose regimen of avelumab plus axitinib in aRCC. Simulated exposure metrics from the previous monotherapy PopPK model (1827 patients) for both weight-based and flat-dose regimens were compared with exposure metrics from treatment-naive patients with aRCC who received avelumab plus axitinib (488 patients). The aRCC population exposures were derived from a fit-for-purpose PopPK model developed using data from monotherapy and combination studies and the existing base structural PopPK model. Exposure-response relationships for safety were analyzed, including grade ≥3 treatment-emergent adverse events (TEAEs), any-grade infusion-related reactions, and TEAE any-grade immune-related adverse events (irAEs). Weight-based dosing of avelumab in the aRCC population yielded similar PK exposures to the flat-dose regimen reference exposures in the monotherapy population. Increased avelumab exposure was not associated with increased probabilities of grade ≥3 TEAEs or any-grade IRRs, although there was a weak association with an increased probability of any-grade irAEs. Overall, models in aRCC suggest that the avelumab 800-mg Q2W flat-dose regimen would provide similar benefits compared with weight-based dosing with no meaningful change in the probability of AEs.

Ensuring diversity in clinical trials: The role of clinical pharmacology.

Increasing the diversity of participants in clinical trials is important as it allows further examination of drug effects in all subgroups of patients who will be prescribed an approved medicine. It also gives patients more confidence in the medicine when they know that individuals similar to themselves have participated in pivotal efficacy and safety trials. Pfizer recently committed to ensuring that its clinical trials reflect racial and ethnic demographics of the patient populations in the countries and communities in which the trials are conducted. This paper furthers Pfizer's commitment by declaring what Clinical Pharmacology (CP) can do to advance this goal and expand patient populations to include other groups such as pediatrics, elderly, and those with organ impairment. This includes steps such as: Pfizer Clinical Pharmacology commits to these actions, which create a framework for the CP Community to enable increased diversity among participants in clinical trials and improved dosing recommendations for all patient subgroups.

A phase 1b/2 study of PF-06747775 as monotherapy or in combination with Palbociclib in patients with epidermal growth factor receptor mutant advanced non-small cell lung cancer.

INTRODUCTION: This Phase 1/2 study (NCT02349633) explored the safety and antitumor activity of PF-06747775 (oral, third-generation epidermal growth factor receptor [EGFR] tyrosine kinase inhibitor) in patients with advanced non-small cell lung cancer after progression on an EGFR inhibitor. METHODS: Phase 1 was a dose-escalation study of PF-06747775 monotherapy (starting dose: 25 mg once daily [QD]). Phase 1b/2 evaluated PF-06747775 monotherapy at recommended Phase 2 dose (RP2D; Cohort 1); PF-06747775 200 mg QD plus palbociclib (starting dose: 100 mg QD orally; Cohort 2A); and PF-06747775 monotherapy at RP2D in a Japanese lead-in cohort. RESULTS: Sixty-five patients were treated. Median treatment duration was 40.1 weeks. Monotherapy maximum tolerated dose was not determined. Two patients in Cohort 2A had dose-limiting toxicities. The monotherapy RP2D was estimated to be 200 mg QD. Most frequently reported adverse events (AEs) were diarrhea (69.2%), paronychia (69.2%), and rash (60.0%). Most AEs were grades 1-3. Overall, objective response rate (90% confidence interval [CI]) was 41.5% (31.2-52.5%). Median (range) duration of response was 11.09 (2.70-34.57) months. Median progression-free survival (90% CI) was 8.1 (5.4-23.3) months. CONCLUSIONS: PF-06747775 had a manageable safety profile and the study design highlights important considerations for future anti-EGFR agent development.

Pharmacokinetics and Safety of Glasdegib in Participants With Moderate/Severe Hepatic Impairment: A Phase I, Single-Dose, Matched Case-Control Study.

This phase I open-label trial (NCT03627754) assessed glasdegib pharmacokinetics and safety in otherwise healthy participants with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment. Participants with hepatic impairment and age/weight-matched controls with normal hepatic function received a single oral 100-mg glasdegib dose under fasted conditions. The primary end points were area under the plasma concentration-time curve from time zero to infinity (AUCinf ) and maximum plasma concentration (Cmax ). Twenty-four participants (8/cohort) were enrolled. Glasdegib plasma exposures in moderate hepatic impairment were similar to controls, with adjusted geometric mean ratios (GMRs) of 110.8% (90% confidence interval [CI], 78.0-157.3) for AUCinf and 94.8% (69.9-128.4) for Cmax versus controls. In severe hepatic impairment, glasdegib plasma exposures were lower than controls (AUCinf GMR, 75.7%; 90%CI, 51.5-111.0; Cmax GMR, 58.0%; 90%CI, 37.8-89.0). Unbound glasdegib exposures were similar to controls for moderate (AUCinf,u GMR, 118.1%; 90%CI, 88.7-157.2; Cmax,u GMR, 101.1%; 90%CI, 78.4-130.3) and severe hepatic impairment (AUCinf,u GMR, 116.3%; 90%CI 81.8-165.5; Cmax,u GMR, 89.2%, 90%CI, 60.2-132.3). No treatment-related adverse events or clinically significant changes in laboratory values, vital signs, or electrocardiograms were observed. Together with previous findings, this suggests glasdegib dose modifications are not required based on hepatic impairment.

Clinical and Model-Based Evaluation of the Effect of Glasdegib on Cardiac Repolarization From a Randomized Thorough QT Study.

Glasdegib is a potent, selective oral inhibitor of the Hedgehog signaling pathway. This phase 1 double-blind thorough QT study (NCT03162900) evaluated the effects of glasdegib on QTc interval. The study enrolled 36 healthy volunteers to receive a single dose of 150 mg glasdegib (representing a therapeutic dose), 300 mg glasdegib (representing a supratherapeutic dose), 400 mg moxifloxacin (positive control), or placebo under fasted conditions. The study demonstrated that therapeutic and supratherapeutic doses of glasdegib had no significant effect on QTc interval; the upper bound of the 2-sided 90% confidence intervals (CIs) for all time-matched least-squares mean differences in QT interval corrected using Fridericia's formula (QTcF) between glasdegib and placebo was below the prespecified criterion of 20 milliseconds (Food and Drug Administration correspondence reviewed and accepted). Based on an exposure-response analysis, glasdegib was determined not to have a meaningful effect on heart rate (change in RR interval). The mean (90%CI) model-derived baseline and placebo-adjusted QTcF at the average maximum observed concentration values corresponding to therapeutic and supratherapeutic glasdegib doses was 7.3 milliseconds (6.5-8.2 milliseconds) and 13.7 milliseconds (12.0-15.5 milliseconds), respectively. Together these results demonstrated that following therapeutic and supratherapeutic glasdegib dosing, the change in QTc from baseline was well below the 20-millisecond threshold of clinical concern in oncology.

Population Pharmacokinetics of Gemtuzumab Ozogamicin in Pediatric Patients with Relapsed or Refractory Acute Myeloid Leukemia.

BACKGROUND AND OBJECTIVE: To date, the population pharmacokinetics (popPK) of gemtuzumab ozogamicin (GO), a CD33-directed antibody-drug conjugate consisting of hP67.6 antibody linked to N-acetyl gamma calicheamicin used in the treatment of acute myeloid leukemia (AML), has not been characterized in pediatric patients. This report describes the popPK of GO following intravenous administration in 29 pediatric patients aged ≤ 17 years with relapsed or refractory AML who were enrolled in the 0903A1-102-US phase I/II study. METHODS: The pharmacokinetics (PK) of GO, as represented by total hP67.6 antibody, were described by a two-compartment model with two clearance components: a linear clearance (CL1) and time-dependent clearance that includes a decay coefficient. The PK of unconjugated calicheamicin (UC; payload) were described by a two-compartment model with CL1 and an input rate of formation based on antibody rate of elimination. Allometric scaling was included in both models, with baseline body weight as a fixed effect on CL1 and central volume. RESULTS AND CONCLUSIONS: PK parameters for hP67.6 and UC were not significantly affected by any of the available demographic factors and safety laboratory values tested as covariates (except baseline body weight). Simulations to compare GO dosing regimens (6, 7.5, and 9 mg/m2 on days 1 and 15 versus, 3 mg/m2 fractionated dosing on days 1, 4, and 7) were performed, showing that total antibody and UC trough concentrations were maintained at higher concentrations during treatment following the more frequent dosing than following the original regimen. STUDY IDENTIFIER: 0903A1-102-US.

Pharmacokinetic/Pharmacodynamic Modeling to Support the Re-approval of Gemtuzumab Ozogamicin.

Gemtuzumab ozogamicin (Mylotarg; Pfizer, New York, NY) was the first antibody-drug conjugate to be approved for CD33-positive acute myeloid leukemia (AML). However, it was voluntarily withdrawn from the US market due to lack of clinical benefit in the confirmatory phase III trial. In 2012, several investigator cooperative studies using a different dosing regimen showed efficacy, but pharmacokinetic (PK) data were not collected in these trials. Through simulation of expected concentrations for new dosing regimens, PK/pharmacodynamic modeling was able to support the safety and efficacy of these regimens. Significant exposure-response relationships were found for the attainment of complete remission with and without platelet recovery, attainment of blast-free status, the time course of myelosuppression, several grade ≥ 3 hepatic adverse events, and veno-occlusive disease. Gemtuzumab ozogamicin received full approval by the US Food and Drug Administration (FDA) in September 2017 for newly diagnosed and relapsed AML in adult patients and relapsed AML in pediatric patients aged 2-17 years.

Effect of food or proton pump inhibitor treatment on the bioavailability of dacomitinib in healthy volunteers.

This phase 1, open-label crossover study evaluated the relative bioavailability of dacomitinib in healthy volunteers under fed and fasted conditions and following coadministration with rabeprazole, a potent acid-reducing proton pump inhibitor (PPI). Twenty-four male subjects received a single dacomitinib 45-mg dose under 3 different conditions separated by washout periods of ≥ 16 days: coadministered with rabeprazole 40 mg under fasting conditions; alone under fasting conditions; and alone after a high-fat, high-calorie meal. Increased peak exposure of 23.7% (90% confidence interval [CI], 5.3%-45.2%) was detected with dacomitinib taken after food versus fasting. The adjusted geometric mean ratio (fed/fasted) for area under the plasma concentration-time curve from time zero to infinity (AUCinf ) was 114.2% (90%CI, 104.7%-124.5%) and not considered clinically meaningful. In the fasted state, a decrease in dacomitinib AUCinf was observed following rabeprazole versus dacomitinib alone (PPI+fasted/fasted alone): 71.1% (90%CI, 61.7%-81.8%). Dacomitinib was generally well tolerated. Dacomitinib may be taken with or without food. Use of long-acting acid-reducing agents, such as PPIs with dacomitinib should be avoided if possible. Shorter-acting agents such as antacids and H2-receptor antagonists may have lesser impact on dacomitinib exposure and may be preferable to PPIs if acid reduction is clinically required.

Drug Interaction between Sirolimus and Ranolazine in a Kidney Transplant Patient.

Purpose. The case of a kidney transplant recipient who experienced a probable drug interaction between sirolimus and ranolazine is reported. Summary. The narrow therapeutic window of immunosuppressive therapy in transplant recipients requires close monitoring for potential drug-drug interactions. The patient, a 57-year-old Caucasian male kidney transplant recipient, was stable for years on sirolimus as his primary immunosuppressive agent and had a history of chronic angina, for which he was prescribed ranolazine. Upon addition and dose escalation of ranolazine, whole blood sirolimus levels more than tripled, rising to immeasurably high concentrations. After holding sirolimus on multiple occasions and reducing dosage more than 50%, blood levels returned to therapeutic range, while continuing ranolazine. Conclusion. Since ranolazine is a documented P-GP and CYP3A inhibitor, and sirolimus a known substrate for both pathways, it is proposed that ranolazine inhibition of P-GP and CYP3A4 contributed to the significant elevation in sirolimus exposure. No alternative causes for the rise in sirolimus exposure were found, and assessment with the Drug Interaction Probability Scale finds this interaction to be probable. Clinicians should be aware of the potential for this interaction to cause elevated sirolimus exposure and subsequent increase in clinical effect or toxicity, in this case overimmunosuppression.