Population pharmacokinetic (PopPK) and physiologically based pharmacokinetic (PBPK) models are frequently used to support pediatric drug development. Both methods have strengths and limitations and we used them complementarily to support the regulatory approval of a dosing algorithm for valganciclovir (VGCV) in children <4 months old. An existing pediatric PBPK model was extended to neonates and showed that potential physiological differences compared with older children are minor. The PopPK model was used to simulate ganciclovir (GCV) exposures in children with population typical combinations of body size and renal function and to assess the effectiveness of an alternative dosing algorithm suggested by the US Food and Drug Administration. PBPK and PopPK confirmed that the proposed VGCV dosing algorithm achieves similar GCV exposures in children of all ages and that the alternative dosing algorithm leads to underexposure in a substantial fraction of patients. Our approach raised the confidence in the VGCV dosing algorithm for children <4 months old and supported the regulatory approval.

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Intravenous ganciclovir and oral valganciclovir are effective in the prevention and treatment of pediatric cytomegalovirus ( CMV ) infection but various dosing regimens are used in medical practice. Population pharmacokinetic (PopPK) model‐based simulations were used to propose a new ganciclovir pediatric dosing algorithm for regulatory review and to evaluate the approved valganciclovir pediatric dosing algorithm against published dosing recommendations derived from quantitative approaches. Oral valganciclovir (mg = 7 × body surface area ( BSA ) × creatinine clearance according to the Schwarz formula (Cr CLS ) daily) and i.v. ganciclovir (mg = 3 × BSA × Cr CLS daily) are effective in reaching ganciclovir target exposure for the prevention of CMV (area under the concentration‐time curve ( AUC ) 0–24 40–60 μg ∙ hour/ mL ) in most pediatric patients across the full pediatric age range. In contrast, ganciclovir and valganciclovir dosing based on body weight, as commonly used in medical practice, leads to underexposure, particularly in younger pediatric patients. This example shows that model‐based dosing algorithms built on clinical pharmacology and implemented using good modeling practice can prevent underexposure and reduce the risk of treatment failure in pediatric patients.

A fixed-dose subcutaneous (s.c.) formulation of the anti-CD20 antibody, rituximab, has been developed to address safety, infusion time, and patient comfort concerns relating to intravenous (i.v.) dosing, and has been approved based upon a pharmacokinetic (PK)-clinical bridging strategy, which demonstrated noninferiority of s.c. vs. i.v. dosing in malignancies, including follicular lymphoma (FL) and chronic lymphocytic leukemia (CLL). A clinical development plan was undertaken to identify rituximab s.c. doses achieving noninferior exposure to rituximab i.v., and to confirm PK-clinical bridging, with the same efficacy and similar safety. This drew upon data from 1,579 patients with FL, CLL, or diffuse large B-cell lymphoma in 5 clinical studies, and showed minimum steady-state serum concentration (C trough ) as the most appropriate exposure bridging measure. Population PK models were developed, simulations were run using covariates and PK parameters from clinical studies, and exposure-efficacy and -safety analyses performed. Population PKs showed a two-compartment model with time-dependent and -independent clearances. Clearance and volume were predominantly influenced by body surface area; disposition and elimination were similar for the s.c. and i.v. formulations. After s.c. administration, patients with FL and CLL achieved noninferior exposures to i.v. dosing. Overall, rituximab exposure and route of administration did not influence clinical responses in patients with FL or CLL, and there was no association between exposure and safety events. C trough was shown to be an effective pharmacologic-clinical bridging parameter for rituximab in patients with FL or CLL. Clinically effective exposures are achieved with either s.c. or i.v. dosing.

Dizziness, the most frequently observed adverse event in patients with major depressive disorder, was observed with basimglurant, a selective, orally active metabotropic glutamate receptor subtype 5 negative allosteric modulator. The potential relationship between dizziness and basimglurant exposure was explored. The pharmacokinetics of basimglurant was characterized with nonlinear mixed effects modeling using data from 288 trial participants enrolled in five clinical trials. The pharmacokinetics of basimglurant after daily oral administration of a modified release formulation was best described by a two‐compartment disposition model with a transit compartment, lag time for the absorption, and first‐order elimination. The largest covariate effects were the effect of smoking and male gender on apparent clearance followed by the effect of body weight on distribution volumes. Clearance was twofold higher in smokers and 40% higher in males. A logistic regression model showed a statistically significant correlation between basimglurant Cmax and incidence of dizziness. An increased risk of dizziness is predicted with increasing doses.