A liquid chromatography‐tandem mass spectrometry method was developed and validated for the simultaneous quantification of vincristine and tariquidar in 10 μL of mouse whole blood using volumetric absorptive microsampling devices. Samples were extracted from the devices and quantified against calibrators prepared in a human blood plasma matrix. Separation of vincristine and tariquidar was achieved using a Shimpack XR ODS III C18 stationary phase and H2O and methanol mobile phase solvents containing 0.1% formic acid, running a gradient elution at a flow rate of 0.2 mL/min over 6.0 min. The method was linear up to 1200 ng/mL (R2 > 0.99 for both analytes), with calibrator accuracy within ± 15% of the nominal concentrations and analyte coefficient of variance <15% for both vincristine and tariquidar. Pharmacokinetic assessment of both analytes was successfully applied in mice as both single‐agent therapy and combination therapy over a 24‐h period, and a 2.3‐fold increase in vincristine drug exposure was observed in combination with tariquidar. This study validates the use of this approach for longitudinal analysis of drug exposure in animal studies.

Aim To investigate the pharmacokinetics (PK) of intravenous treosulfan in paediatric patients undergoing haematopoietic stem cell transplantation (HSCT) for a broad range of diseases and to explore the impact of different dosing regimens on treosulfan exposure (area under the concentration–time curve, AUC0→∞) through dosing simulations. Methods A prospective multicentre PK study was conducted using treosulfan concentration data (n = 423) collected from 53 children (median age 3.5, range 0.2–17.0 years) receiving three daily age‐guided doses (10–14 g/m2). Population PK modelling was performed using NONMEM software, utilising a stepwise forward selection backward elimination method and likelihood‐ratio test for screening covariates to describe PK variability. Monte Carlo simulation was used to generate patient PK data for 10 000 virtual paediatric patients and cumulative AUC0→∞ values were evaluated using age, body surface area (BSA) and model‐based dosing regimens, targeting 4800 mg*h/L. Results Treosulfan concentration data were described using a one‐compartment PK model with first‐order elimination. Population mean (95% CI) estimates for clearance (CL) and volume of distribution (V) were 16.3 (14.9–18.1) L/h and 41.9 (38.8–45.1) L, respectively. Allometrically scaled body weight was the best covariate descriptor for CL and V, and maturational age further explained variability in CL. Dosing simulations indicated that in young patient groups (<2 years), a model‐based dosing regimen more accurately achieved the target AUC0→∞ (58.3%) over the age (42.6%) and BSA‐based (51.3%) regimens. Conclusion Treosulfan disposition was described through allometric body weight and maturational age descriptors. Model‐informed dosing is recommended for patients under 2 years. Treosulfan PK parameters and AUC0→∞ were not influenced by patient disease.

N,N–dimethylacetamide is an excipient used in intravenous busulfan formulations, a drug used in hematopoietic stem cell transplantation conditioning. The aim of this study was to develop and validate a liquid chromatography‐tandem mass spectrometry method for simultaneous quantification of N,N‐dimethylacetamide, and its metabolite N‐monomethylacetamide in plasma from children receiving busulfan. A 4 μl aliquot of patient plasma was extracted using 196 μl 50% methanol solution and quantified against calibrators prepared in the extraction solvent given negligible matrix effects across three concentrations. 9[H2]‐N,N‐dimethylacetamide was used as an internal standard. Separation of N,N‐dimethylacetamide and N‐monomethylacetamide was achieved using a Kinetex EVO C18 stationary phase (100 mm × 2.1 mm × 2.6 μm) running an isocratic mobile phase of 30% methanol containing 0.1% formic acid at a flow of 0.2 ml/min over 3.0 min. The injection volume was 1 μl. Calibration curves for N,N‐dimethylacetamide and N‐monomethylacetamide were linear up to 1200 and 200 μg/L, respectively, with a lower limit of quantification 1 μg/L for both analytes. Calibrator accuracy and precision were within ± 10% of the test parameters across four concentration levels. Analytes were stable over 14 days at three different storage conditions. This method was successfully applied to measure N,N‐dimethylacetamide and N‐monomethylacetamide concentrations in a total of 1265 plasma samples from 77 children.