Vincristine (VCR) is frequently used in pediatric oncology and can be administered intravenously through push injections or 1 h infusions. The effects of administration duration on population pharmacokinetics (PK) are unknown. We described PK differences related to administration duration and the relation between PK and VCR-induced peripheral neuropathy (VIPN). PK was assessed in 1–5 occasions (1–8 samples in 24 h per occasion). Samples were analyzed using high-performance liquid chromatography/tandem mass spectrometry. Population PK of VCR and its relationship with administration duration was determined using a non-linear mixed effect. We estimated individual post-hoc parameters: area under the concentration time curve (AUC) and maximum concentration (C_max) in the plasma and peripheral compartment. VIPN was assessed using Common Terminology Criteria for Adverse Events (CTCAE) and the pediatric-modified total neuropathy score (ped-mTNS). Overall, 70 PK assessments in 35 children were evaluated. The population estimated that the intercompartmental clearance (IC-Cl), volume of the peripheral compartment (V₂), and C_max were significantly higher in the push group. Furthermore, higher IC-Cl was significantly correlated with VIPN development. Administration of VCR by push led to increased IC-Cl, V₂, and C_max, but were similar to AUC, compared to 1 h infusions. Administration of VCR by 1 h infusions led to similar or higher exposure of VCR without increasing VIPN.

Renal function-based carboplatin dosing using measured glomerular filtration rate (GFR) results in more consistent drug exposure than anthropometric dosing. We aimed to validate the Newell dosing equation using estimated GFR (eGFR) and study which equation most accurately predicts carboplatin clearance in children with retinoblastoma. In 13 children with retinoblastoma 38 carboplatin clearance values were obtained from individual fits using MWPharm++. Carboplatin exposure (AUC) was calculated from administered dose and observed carboplatin clearance and compared to predicted AUC calculated with a carboplatin dosing equation (Newell) using different GFR estimates. Different dosing regimens were compared in terms of accuracy, bias and precision. All patients had normal eGFR. Carboplatin exposure using cystatin C-based eGFR equations tended to be more accurate compared to creatinine-based eGFR (30% accuracy 76.3–89.5% versus 76.3–78.9%, respectively), which led to significant overexposure, especially in younger (aged ≤ 2 years) children. Of all equations, the Schwartz cystatin C-based equation had the highest accuracy and lowest bias. Although anthropometric dosing performed comparably to many of the eGFR equations overall, we observed a weight-dependent change in bias leading to underdosing in the smallest patients. Using cystatin C-based eGFR equations for carboplatin dosing in children leads to more accurate carboplatin-exposure in patients with normal renal function compared to anthropometric dosing. In children with impaired kidney function, this trend might be more pronounced. Anthropometric dosing is hampered by a weight-dependent bias.

Background/Objectives: Ambroxol hydrochloride (AMB) is a promising chaperone for treating neurological manifestations in Gaucher disease type 3 (GD3). The Amsterdam University Medical Center planned to conduct an n-of-1 clinical trial using high-dose AMB (25 mg/kg/day). As an adequate commercial AMB formulation is unavailable for this high target dosage, we aimed to develop high-dose AMB capsules and assess the formulated capsule’s quality. Methods: AMB API was sourced and tested according to the requirements of the European Pharmacopoeia. Capsule formulations of 75 mg and 200 mg AMB were developed. Drug product specifications were set following international guidelines (ICH Q6A) and the European Pharmacopoeia. Analytical methods were developed and validated, and three validation batches of each capsule strength were produced and analyzed. Results: The contents and the Acceptance Values (AVs) of the initial AMB batches (both strengths) varied between 89.1% to 92.7% (specification: 90% to 110%) and 12.4 to 17.6 (specification ≤ 15.0), respectively, indicating non-uniform AMB distribution. Consequently, the production of 200 mg capsules was discontinued, and modifications were made to the 75 mg capsule formulation, followed by the production of three optimized 75 mg validation batches. These batches met the specified criteria, with an AMB content and AV values ranging from 93.9% to 96.5% and 12.4 to 14.9, respectively. Furthermore, rapid dissolution profiles were observed (>80% dissolution within 15 min). No degradation products or microbiological impurities were detected after production. Conclusions: The optimized formulation of 75 mg AMB capsules formulated within the hospital pharmacy setting resulted in qualitative and uniform capsules which can be used in clinical trials.