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Teduglutide is a recombinant analog of human glucagon‐like peptide‐2 that regulates the functional and structural integrity of the cells lining the gastrointestinal tract. Teduglutide is approved for the treatment of patients with short bowel syndrome (SBS) who are dependent on parenteral support (PS). Population pharmacokinetic (PK) and exposure‐response analyses were performed to support teduglutide dosing in patients with SBS. The analysis included 219 patients with SBS (aged

Aim The aim of the present study was to evaluate the pharmacokinetics of bevacizumab and various dosing strategies for this agent in paediatric patients. Methods Data were collected from 232 paediatric patients (1971 concentrations) in five studies, with a wide range of age (0.5 – 21 years), body weight (BWT; 5.9 – 125 kg), and regimens (5 – 15 mg kg–1 biweekly or triweekly). Data from 152 patients (1427 concentrations) and 80 patients (544 concentrations) were used for model building and external validation, respectively. Steady‐state exposure was simulated under BWT‐based, body surface area (BSA)‐based, ideal body weight (IBW)‐based, and tier‐based doses. NONMEM and R were used for analyses. Results Typical estimates of clearance, central volume of distribution (V1), and median half‐life were 9.04 ml h–1, 2851 ml, and 19.6 days, respectively. Clearance decreased with increasing albumin. Clearance and V1 increased with BWT and were higher in male patients. Clearance and V1 were lower in children with primary central nervous system (CNS) tumours than in children with sarcomas, resulting in 49% higher trough (Cmin) and 29% higher peak (Cmax) concentrations. BWT‐adjusted clearance and V1 remained unchanged across ages. Paediatric Cmin was similar to adult Cmin under all dosing strategies. Paediatric Cmax exceeded adult Cmax under tier‐based doses. Conclusions BWT‐adjusted pharmacokinetic parameter estimates in paediatric patients were similar to those in adults, and similar across ages. Bevacizumab exposure was higher in children with primary CNS tumours than in children with sarcomas. BSA‐based, IBW‐based, and tier‐based doses offered no substantial advantage over the BWT‐based dose currently used in adults for bevacizumab. Given the similarity in pharmacokinetics among many monoclonal antibodies, this may help to develop practical paediatric dosing guidelines for other therapeutic antibodies.

X-linked hypophosphatemia (XLH) is an inherited metabolic bone disease with abnormally elevated serum FGF23 resulting in low renal maximum threshold for phosphate reabsorption, low serum phosphate (Pi) and 1,25-dihydroxyvitamin D levels with subsequent development of short stature and skeletal deformities. KRN23 is a novel human anti-FGF23 antibody for the treatment of XLH. The pharmacokinetics (PK) and pharmacodynamics (PD) models of KRN23 were assessed following subcutaneous dosing every 28 days over an initial 4-month dose escalation (0.05-0.6 mg/kg) and a subsequent 12-month titration period (0.1-1.0 mg/kg) in XLH adults. The PK of KRN23 was described by a 1-compartmental model with first-order absorption and elimination at doses ≥0.1 mg/kg. The elimination half-life was 17.8 days. Covariates did not affect KRN23 PK. Mean peak serum Pi was attained 7-10 days after dosing and progressively increased following each of the initial 4 doses with comparable peak values attained following the sixth through tenth doses with a slight decrease thereafter. A PK-PD model with a maximum effect (Emax ) and a time-varying effective concentration to reach 50% of Emax (EC50,t ) described data adequately. Typical Emax was 1.5 mg/dL. Typical EC50,t was 1780 ng/mL and 5999 ng/mL after first and last dose, respectively.

Background Bevacizumab is approved for various cancers. This analysis aimed to comprehensively evaluate bevacizumab pharmacokinetics and the influence of patient variables on bevacizumab pharmacokinetics. Methods Rich and sparse bevacizumab serum concentrations were collected from Phase I through IV studies in early and metastatic cancers. Bevacizumab was given intravenously as single agent or in combination with chemotherapy for single- and multiple-dose schedules. Results Model-building used 8943 bevacizumab concentrations from 1792 patients with colon/colorectal, non-small cell lung, kidney, pancreatic, breast, prostate and brain cancer. Bevacizumab doses ranged from 1 to 20 mg/kg given once every 1, 2 or 3 weeks. A two-compartment model best described the data. The population estimates of clearance (CL), central volume of distribution (V1) and half-life for a typical 70-kg patient were 9.01 mL/h, 2.88 L and 19.6 days. CL and V1 increased with body weight and were higher in males than females by 14 and 18 %, respectively. CL decreased with increasing albumin and decreasing alkaline phosphatase. The final model was externally validated using 1670 concentrations from 146 Japanese patients that were not used for model-building. Mean prediction errors were −2.1, 3.1 and 1.0 % for concentrations, CL and V1, respectively, confirming adequate predictive performance. Conclusions A robust bevacizumab pharmacokinetic model was developed and externally validated, which may be used to simulate bevacizumab exposure to optimize dosing strategies. Asian and non-Asian patients exhibited similar bevacizumab pharmacokinetics. Given the similarity in pharmacokinetics among monoclonal antibodies, this may inform pharmacokinetic studies in different ethnic groups for other therapeutic antibodies. Electronic supplementary material The online version of this article (doi:10.1007/s00280-016-3079-6) contains supplementary material, which is available to authorized users.