L-praziquantel (PZQ) pharmacokinetic data were analyzed from two relative bioavailability Phase 1 studies in adult, healthy subjects with two new oral dispersion tablet (ODT) formulations of L-PZQ administered under various combinations of co-administration with food, water, and/or crushing. Linear mixed effects models adequately characterized the noncompartmental estimates of the pharmacokinetic profiles in both studies. Dose, food, and formulation were found to significantly affect L-PZQ exposure in both studies. The model for AUC was then extrapolated to children 2–5 years old accounting for enzyme maturation and weight. The predicted exposures were compared to an external Phase 1 study conducted by the Swiss Tropical and Public Health Institute using a currently marketed formulation (Cesol 600 mg immediate-release tablets) and found to be substantially lower than observed. A root cause analysis was completed to identify the reason for failure of the models. Various scenarios were proposed and tested. Two possible reasons for the failure were identified. One reason was that the model did not account for the reduced hepatic clearance seen in patients compared to the healthy volunteer population used to build the model. The second possible reason was that PZQ absorption appears sensitive to meal composition and the model did not account for differences in meals between a standardized Phase 1 unit and clinical sites in Africa. Further studies are needed to confirm our hypotheses.Electronic supplementary materialThe online version of this article (10.1007/s10928-018-9601-1) contains supplementary material, which is available to authorized users.

To evaluate the safety, tolerability, efficacy, pharmacokinetics and pharmacodynamics of the humanised antiepidermal growth factor receptor monoclonal antibody matuzumab combined with epirubicin, cisplatin and capecitabine (ECX) in patients as first-line treatment for advanced oesophagogastric cancer that express epidermal growth factor receptor (EGFR). This was a phase I dose escalation study of matuzumab at 400 and 800 mg weekly and 1200 mg every 3 weeks combined with ECX (epirubicin 50 mg m À2 , cisplatin 60 mg m À2 on day 1 and capecitabine 1000 mg m À2 daily). Patients were treated until disease progression, unacceptable toxicity or for a maximum of eight cycles. Twenty-one patients were treated with matuzumab at three different dose levels (DLs) combined with ECX. The main dose-limiting toxicity (DLT) was grade 3 lethargy at 1200 mg matuzumab every 3 weeks and thus 800 mg matuzumab weekly was the maximum-tolerated dose (MTD). Other common toxicities included rash, nausea, stomatitis and diarrhoea. Pharmacokinetic evaluation demonstrated that the coadministration of ECX did not alter the exposure of matuzumab. Pharmacodynamic studies on skin biopsies demonstrated inhibition of the EGFR pathway. Objective response rates of 65% (95% confidence interval (CI): 43 -82), disease stabilisation of 25% (95% CI: 11 -47) and a disease control rate (CR þ PR þ SD) of 90% were achieved overall. The MTD of matuzumab in combination with ECX was 800 mg weekly, and at this DL it was well-tolerated and showed encouraging antitumour activity. At the doses evaluated in serial skin biopsies, matuzumab decreased phosphorylation of EGFR and MAPK, and increased phosphorylation of STAT-3.

Background. The purpose of this study was to assess the efficacy, safety, and pharmacokinetics of cisplatin-based chemotherapy plus cetuximab as first-line treatment in Chinese and Korean patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN). Methods. Patients (n 5 68) received cetuximab weekly plus 3-week cycles of cisplatin/5-fluorouracil (5-FU) chemotherapy for up to 6 cycles. The primary endpoint was overall response rate. Results. The overall response rate was 55.9%, including 2 complete responses (CRs). Median overall survival (OS) was 12.6 months and median progression-free survival (PFS) was 6.6 months. Grade 3/4 adverse events (AEs) were reported in 41 (60.3%) patients. The safety profile was in line with previous clinical experience. The pharmacokinetic profile was in line with that observed with cetuximab in white and Japanese patients. Conclusion. The efficacy, safety, and pharmacokinetic findings from this study support the use of first-line platinum-based chemotherapy plus cetuximab in Chinese and Korean patients with recurrent and/or metastatic SCCHN (ClinicalTrials.gov NCT01177956).

A population pharmacokinetic model based on data from three phase I studies was to be developed including a covariate analysis to describe the concentration -time profiles of matuzumab, a novel humanised monoclonal antibody. Matuzumab was administered as multiple 1 h i.v. infusions with 11 different dosing regimens ranging from 400 to 2000 mg, q1w -q3w. For analysis, 90 patients with 1256 serum concentration -time data were simultaneously fitted using the software NONMEMt. Data were best described using a two-compartment model with the parameters central (V 1 ) and peripheral distribution volume (V 2 ), intercompartmental (Q) and linear (CLL) clearance and an additional nonlinear elimination pathway (K m , V max ). Structural parameters were in agreement with immunoglobulin characteristics. In total, interindividual variability on V max , CLL, V 1 and V 2 and interoccasion variability on CLL was 22 -62% CV. A covariate analysis identified weight having an influence on V 1 ( þ 0.44% per kg) and CLL ( þ 0.87% per kg). All parameters were estimated with good precision (RSEo39%). A robust population pharmacokinetic model for matuzumab was developed, including a nonlinear pharmacokinetic process. In addition, relevant and plausible covariates were identified and incorporated into the model. When correlated to efficacy, this model could serve as a tool to guide dose selection for this 'targeted' cancer therapy.

Physiologically based pharmacokinetic (PBPK) modeling integrates physicochemical (PC) and in vitro pharmacokinetic (PK) data using a mechanistic framework of principal ADME (absorption, distribution, metabolism, and excretion) processes into a physiologically based whole-body model. Absorption, distribution, and clearance are modeled by combining compound-specific PC and PK properties with physiological processes. Thereby, isolated in vitro data can be upgraded by means of predicting full concentration-time profiles prior to animal experiments. The integrative process of PBPK modeling leads to a better understanding of the specific ADME processes driving the PK behavior in vivo, and has the power to rationally select experiments for a more focussed PK project support. This article presents a generic disposition model based on tissue-composition-based distribution and directly scaled hepatic clearance. This model can be used in drug discovery to identify the critical PK issues of compound classes and to rationally guide the optimization path of the compounds toward a viable development candidate. Starting with a generic PBPK model, which is empirically based on the most common PK processes, the model will be gradually tailored to the specifics of drug candidates as more and more experimental data become available. This will lead to a growing understanding of the 'drug in the making', allowing a range of predictions to be made for various purposes and conditions. The stage is set for a wide penetration of PK modeling and simulations to form an intrinsic part of a project starting from lead discovery, to lead optimization and candidate selection, to preclinical profiling and clinical trials.