Lean body mass and total body weight versus body surface area as determinant of docetaxel pharmacokinetics and toxicity

Aim: In our study we examined whether anthropometric and body composition parameters, i.e. body surface area (BSA), lean body mass (LBM) and total body weight (TBW), are correlated with docetaxel clearance and exposure. In addition, LBM, TBW and a fixed dose were compared to BSA as dosing parameters for dose individualisation of docetaxel. Methods: Thirty-six patients affected by breast or castration-resistant prostate carcinoma receiving docetaxel chemotherapy entered the study. LBM was measured by a Dual Energy Xray Absorptiometry (DEXA) scanner before treatment. Blood samples were collected up to 180 minutes after dosing to analyse docetaxel concentrations and to determine individual pharmacokinetic (PK) parameters. Results: No significant correlations were found between the docetaxel pharmacokinetic parameters clearance and volume of distribution and the anthropometric and body composition variables BSA, LBM and TBW. AUC was significantly but poorly correlated with BSA (r=0.452 [p=0.016]) and with TBW (r=0.476 (p=0.011]). The Mean Absolute Percentage Error and Mean Error of simulated dosing based on LBM and fixed dosing ME were not significant different compared to BSA. For TBW, only the MAPE of dosing was significant higher compared to BSA (24.1 vs. 17.1, P=0.001). Conclusion: There is no correlations between docetaxel pharmacokinetics and the anthropometric and body composition variables BSA, LBM and TBW. Dose individualisation of docetaxel based on LBM or TBW or fixed dosing cannot be recommended over BSA based dosing.

Plasma concentration guided dosing of drugs used for the treatment of childhood leukaemias: protocol for a systematic review

IntroductionChildhood leukaemia is the most common type of cancer in children and represents among 25% of the diagnoses in children <15 years old. Childhood survival rates have significantly improved within the last 40 years due to a rapid advancement in therapeutic interventions. However, in high-risk groups, survival rates remain poor. Pharmacokinetic (PK) data of cancer medications in children are limited and thus current dosing regimens are based on studies with small sample sizes. In adults, large variability in PK is observed and dose individualisation (plasma concentration guided dosing) has been associated with improved clinical outcomes; whether this is true for children is still unknown. This provides an opportunity to explore this strategy in children to potentially reduce toxicities and ensure optimal dosing. This paper will provide a protocol to systematically review studies that have used dose individualisation of drugs used in the treatment of childhood leukaemias.Methods and analysisSystematic review methodology will be applied to identify, select and extract data from published plasma guided dosing studies conducted in a paediatric leukaemia cohort. Databases (eg, Ovid Embase, Ovid MEDLINE, Ovid Cochrane) and clinical trial registries (CENTRAL, ClinicalTrials.gov and ISRCTN) will be used to perform the systematic literature search (up until February 2021). Only full empirical studies will be included, with primary clinical outcomes (progression-free survival, toxicities, minimal residual disease status, complete cytogenetic response, partial cytogenetic response and major molecular response) being used to decide whether the study will be included. The quality of included studies will be undertaken, with a subgroup analysis where appropriate.Ethics and disseminationThis systematic review will not require ethics approval as there will not be collection of primary data. Findings of this review will be made available through publications in peer-reviewed journals and conference presentations. Gaps will be identified in current literature to inform future-related research.PROSPERO registration numberCRD42021225045.

Dose Banding -- weighing up benefits, therapeutic failure and risks

Aim Dose banding is a commonly used method of dose individualisation in which all patients with similar characteristics are allocated to the same dosing group. Dose banding results in some patients receiving less intensive treatment with the potential for a reduction in therapeutic benefit (iatrogenic therapeutic failure). This study aims to explore the effects of dose banding on therapeutic success and failure. Methods This was a simulation study conducted using MATLAB. Virtual patients were simulated under a simple pharmacokinetic model with a predefined target steady-state average concentration (c_(ss,ave)). Clearance was correlated with a covariate used for dosing. Dose individualisation was based on: one-dose-fits-all, covariate based dosing, empirical dose banding, dose banding optimised for benefit:risk only and dose banding optimised for both benefit:risk and minimising iatrogenic therapeutic failure. Results The lowest and highest probabilities of target attainment (PrTA) were 46% for one-dose-fits-all and 72% for fully individualised covariate-based dosing. Neither dosing approach would result in iatrogenic therapeutic failure as lower dose intensities do not occur. Empirical dose banding performed better than once-dose-fits-all with 59% PTA but not as good as either optimised method (64-69% PrTA) while carrying a risk of iatrogenic therapeutic failure in 25% of patients. Optimising for benefit:risk (only) improved PrTA but carried a risk of iatrogenic therapeutic failure of up to 10%. Optimising for benefit:risk and minimising iatrogenic therapeutic failure provided the best balance. Conclusion Future application of dose banding needs to consider both the probability of benefit:risk as well the risk of causing iatrogenic therapeutic failure.

Concept and utility of population pharmacokinetic and pharmacokinetic/pharmacodynamic models in drug development and clinical practice

Due to frequent clinical trial failures and consequently fewer new drug approvals, the need for improvement in drug development has, to a certain extent, been met using model-based drug development. Pharmacometrics is a part of pharmacology that quantifies drug behaviour, treatment response and disease progression based on different models (pharmacokinetic - PK, pharmacodynamic - PD, PK/PD models, etc.) and simulations. Regulatory bodies (European Medicines Agency, Food and Drug Administration) encourage the use of modelling and simulations to facilitate decision-making throughout all drug development phases. Moreover, the identification of factors that contribute to variability provides a basis for dose individualisation in routine clinical practice. This review summarises current knowledge regarding the application of pharmacometrics in drug development and clinical practice with emphasis on the population modelling approach.