Introduction Pharmacokinetic outcomes of transporter-mediated drug-drug interactions (TMDDIs) are increasingly being evaluated clinically. The goal of our study was to determine the effects of selective inhibition of multi-drug and toxin extrusion protein 1 (MATE1) using famotidine, on the pharmacokinetics and pharmacodynamics of metformin in healthy volunteers. Methods Volunteers received metformin alone or with famotidine in a crossover design. As a positive control, the longitudinal effects of famotidine on the plasma levels of creatinine (an endogenous substrate of MATE1) were quantified in parallel. Famotidine unbound concentrations in plasma reached 1 μM, thus exceeding the in vitro concentrations that inhibit MATE1 (IC50 0.25 μM). Based on current regulatory guidance, these concentrations are expected to inhibit MATE1 clinically (i.e., Cmax,u/IC50 >0.1). Results Consistent with MATE1 inhibition, famotidine administration significantly altered creatinine plasma and urine levels in opposing directions (P<0.005). Interestingly, famotidine increased the estimated bioavailability of metformin (Ae∞/Dose, P < 0.005) without affecting its systemic exposure (AUC or Cmax) as a result of a counteracting increase in metformin renal clearance. Moreover, metformin-famotidine co-therapy caused a transient effect on oral glucose tolerance tests (AUCglu,0.5, P < 0.005). Conclusions These results suggest that famotidine may improve the bioavailability and enhance the renal clearance of metformin.

Rationale: Rifapentine has been investigated at various doses, frequencies, and dosing algorithms but clarity on the optimal dosing approach is lacking. Objectives: In this individual participant data meta-analysis of rifapentine pharmacokinetics, we characterize rifapentine population pharmacokinetics, including autoinduction, and determine optimal dosing strategies for short-course rifapentine-based regimens for latent tuberculosis infection. Methods: Rifapentine pharmacokinetic studies were identified though a systematic review of literature. Individual plasma concentrations were pooled, and non-linear mixed effects modeling was performed. A subset of data was reserved for external validation. Simulations were performed under various dosing conditions including current weight-based methods and alternative methods driven by identified covariates. Measurements and Main Results: We identified 9 clinical studies with a total of 863 participants with pharmacokinetic data (n=4301 plasma samples). Rifapentine population pharmacokinetics were described successfully with a one-compartment distribution model. Autoinduction of clearance was driven by rifapentine plasma concentration. The maximum effect was a 72% increase in clearance and was reached after 21 days. Drug bioavailability decreased by 27% with HIV infection, decreased by 28% with fasting, and increased by 49% with a highfat meal. Body weight was not a clinically relevant predictor of clearance. Pharmacokinetic simulations showed that current weight-based dosing leads to lower exposures in low weight individuals, which can be overcome with flat dosing. In HIV-positive patients, 30% higher doses are required to match drug exposure in HIV-negative patients. 2 Conclusions: Weight-based dosing of rifapentine should be removed from clinical guidelines and higher doses for HIV-positive patients should be considered to provide equivalent efficacy.

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.

Total hP67.6 antibody disposition did not appear altered in patients with mild or moderate renal disease or hepatic impairment. Gemtuzumab ozogamicin was approved for the treatment of acute myeloid leukemia by the US Food and Drug Administration in September 2017. The model-based simulations described here provided a pharmacokinetic rationale for the approved dosing regimen of 3 mg/m on days 1, 4, and 7, and served as the basis for all exposure-response modeling included in the recent Biologics License Application submission. Clinical trials identifiers: 0903A1-101-US; 0903A1-103-JA; 0903B1-201-US/CA (NCT00003131); 0903B1-202-EU; 0903B1-203-US/EU (NCT00003673); 0903B1-205-US/EU/AU (NCT00037596); and 0903B1-206-US/EU/AU (NCT00037583).

BACKGROUND: Avelumab, a monoclonal antibody targeting PD-L1, was recently approved in the United States for first-line maintenance (1LM) treatment of patients with locally advanced or metastatic urothelial carcinoma (UC) that has not progressed with first-line platinum-containing chemotherapy. This analysis assessed the potential relationship between covariates, including avelumab exposure, and overall survival (OS) in patients with UC. METHODS: This analysis included all patients (N=350) who received avelumab 10 mg/kg every 2 weeks (Q2W) + best supportive care (BSC; arm A) in the JAVELIN Bladder 100 study (intention-to-treat population). Exposure metrics were derived based on a separate population pharmacokinetic model. The exposure-response analyses were conducted using parametric time-to-event (TTE) methodology, and the distribution of survival vs time was tested using exponential, Weibull, log-normal, and log-logistic distributions. A stepwise covariate search was conducted to determine the full and final models (forward addition α=0.05; backward elimination α=0.01). Model adequacy and predictability were evaluated using TTE-visual predictive checks and the likelihood ratio test. RESULTS: The best fit to the hazard distribution was the log-normal distribution. Avelumab exposure (cycle 1 day 15 trough concentration) was associated with a higher probability of longer OS in both univariate and multivariate regression models. Nonvisceral metastatic disease at the time of initiating first-line chemotherapy was associated with higher probability of longer OS compared with visceral metastasis; this was a study stratification factor and a known predictor of OS in this population. Hemoglobin was also identified as a predictor of OS, consistent with previous reports. However, several factors may have confounded the interpretation of the exposure-OS modeling results, including an imbalance of baseline health status across the exposure quartiles, eg, Eastern Cooperative Oncology Group performance status (ECOG PS) and body weight, and that the data were from a single-dose regimen. Covariates that were not identified as predictors of OS were antidrug antibody status, Asian race, age, sex, smoking history, baseline ECOG PS, best response to first-line chemotherapy, and first-line chemotherapy regimen (α=0.01). CONCLUSION: The E-R analyses were considered exploratory and no definite conclusions could be made on the impact of exposure on OS, as other variables confounded the relationship. Overall, the exposure from avelumab 10 mg/kg IV Q2W + BSC was associated with a manageable safety and tolerability profile and demonstrated superior efficacy compared with BSC alone in terms of OS as 1LM in patients with UC. Citation Format: Jennifer Hibma, Jerry Li, Carlo Bello, Akash Khandelwal, Yulia Vugmeyster, Dana Nickens, Swan Li. Exposure-response (E-R) analysis of efficacy for avelumab as first-line maintenance therapy for urothelial carcinoma in the JAVELIN Bladder 100 study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1362.