We propose a model that characterizes and links the complexity and diversity of clinically observed hepatitis C viral kinetics to sustained virologic response (SVR)—the primary clinical end point of hepatitis C treatment, defined as an undetectable viral load at 24 weeks after completion of treatment)—in patients with chronic hepatitis C (CHC) who have received treatment with peginterferon α‐2a ± ribavirin. The new attributes of our hepatitis C viral kinetic model are (i) the implementation of a cure/viral eradication boundary, (ii) employment of all hepatitis C virus (HCV) RNA measurements, including those below the lower limit of quantification (LLOQ), and (iii) implementation of a population modeling approach. The model demonstrated excellent positive (99.3%) and negative (97.1%) predictive values for SVR as well as high sensitivity (96.6%) and specificity (99.4%). The proposed viral kinetic model provides a framework for mechanistic exploration of treatment outcome and permits evaluation of alternative CHC treatment options with the ultimate aim of developing and testing hypotheses for personalizing treatments in this disease. Clinical Pharmacology & Therapeutics (2010) 87 6, 706–713. doi:

A two‐analyte integrated population pharmacokinetic (PK) model that simultaneously describes concentrations of antibody‐conjugated monomethyl auristatin E (acMMAE) and unconjugated MMAE following repeated administrations of polatuzumab vedotin (pola) was developed based on data from four clinical studies of pola in patients with non‐Hodgkin lymphoma. A two‐compartment model with a nonspecific, time‐dependent linear clearance, a linear time‐dependent exponentially declining clearance, and a Michaelis–Menten clearance provided a good fit of the acMMAE plasma PK profiles. All three acMMAE elimination pathways contributed to the input to the central compartment of unconjugated MMAE, which was also described by a two‐compartment model. Population PK parameters, covariate effects, and interindividual variability of model parameters were estimated. The impact of clinically relevant covariates on PK exposures of each analyte were quantified and reported to support key label claims.

Oseltamivir is a potent, selective, oral neuraminidase inhibitor for the treatment and prophylaxis of influenza. Plasma concentrations of the active metabolite, oseltamivir carboxylate, are increased in the presence of probenecid, suggesting that the combination could allow for the use of reduced doses of oseltamivir. To investigate this proposal, we developed a population pharmacokinetic model and simulated the pharmacokinetics of candidate combination regimens of oral oseltamivir (45 mg and 30 mg twice a day) plus oral probenecid (500 mg/6 hourly). Probenecid plus oseltamivir 45 mg achieved all the pharmacokinetic parameters expected of oseltamivir alone, but combination with oseltamivir 30 mg and dose interval extension approaches did not. An oseltamivir-probenecid combination may compromise tolerability and enhance the potential for drug interactions. In addition, increased dosing requirements may affect compliance and attainment of optimal oseltamivir exposure, potentially facilitating the emergence of viral strains with reduced susceptibility to oseltamivir. These factors, set alongside increased capacity for oseltamivir production, should be carefully considered before an oseltamivir-probenecid combination is used.

BackgroundThe iMATRIX-atezolizumab study was a phase I/II, multicenter, open-label study designed to assess the safety and pharmacokinetics of atezolizumab in pediatric and young adult patients. We describe the pharmacokinetics (PK), exposure-safety, and immunogenicity of atezolizumab in pediatric and young adults with metastatic solid tumors or hematologic malignancies enrolled in this study.MethodsPatients aged < 18 years (n = 69) received a weight-adjusted dose of atezolizumab (15 mg/kg every 3 weeks [q3w]; maximum 1200 mg); those aged ≥ 18 years (n = 18) received a flat dose (1200 mg q3w). A prior two-compartment intravenous infusion input adult population-PK (popPK) model of atezolizumab was used as a basis to model pediatric data.ResultsA total of 431 atezolizumab serum concentrations from 87 relapse-refractory pediatric and young adult patients enrolled in the iMATRIX-atezolizumab study were used for the popPK analysis. The dataset comprised predominantly patients aged < 18 years, including two infants aged < 2 years, with a wide body weight and age range. The clearance and volume of distribution estimates of atezolizumab were 0.217 L/day and 3.01 L, respectively. Atezolizumab geometric mean trough exposures were ~ 20% lower in pediatric patients versus young adults; this was not clinically meaningful as both groups achieved the target concentration (6 μg/mL). Safety was similar between pediatric and young adult patients with no exposure-safety relationship observed. Limited responses (4/87) precluded an exposure-response assessment on outcomes. A comparable rate (13% vs 11%) of atezolizumab anti-drug antibodies was seen in pediatric and young adult patients.ConclusionsThese findings demonstrate a similar exposure-safety profile of atezolizumab in pediatric and young adult patients, supportive of weight-based dosing in pediatric patients.Trial registrationNCT02541604.

This study aimed to develop a population pharmacokinetic/pharmacodynamic (PK/PD) model for C.E.R.A., a continuous erythropoietin receptor activator. C.E.R.A. is administered via intravenous (IV) and subcutaneous (SC) routes once every 2 weeks (Q2W) or once every 4 weeks (Q4W), respectively, to correct or maintain hemoglobin levels in chronic kidney disease (CKD) patients. Population models were specified to describe C.E.R.A. (PK) and hemoglobin (PD) concentrations over time, using data from 3 phase III, open-label, randomized, parallel-group, multicenter studies that examined IV or SC C.E.R.A. administration Q2W and Q4W in erythropoiesis-stimulating agent (ESA)-naive and ESA-treated patients. C.E.R.A. PK was described by a 1-compartment model: drug clearance = 0.75 L/d, volume of distribution = 4.72 L, and half-life = 105 hours in accordance with previous reported values. The PD model, a life span sequential PK/PD model, adequately described hemoglobin data. Dosing schedule, administration route, and study type did not affect drug-related PD parameters or system-specific parameters (eg, red blood cell life span). This model adequately described C.E.R.A.'s PK and PD properties according to C.E.R.A. posology, thus permitting simulations exploring alternative drug administration scenarios. It supports use of C.E.R.A. IV and SC; Q2W for anemia correction in ESA-Naïve CKD patients and monthly administration in the hemoglobin maintenance phase.