Pharmacokinetic-pharmacodynamic modelling of atazanavir in hair among adolescents on antiretroviral treatment in Zimbabwe

Bernard Ngara,Simbarashe Rusakaniko,Simbarashe Zvada,Tariro Dianah Chawana,Charles Fungai Brian Nhachi

doi:10.1186/s40360-021-00497-8

Bernard Ngara, Simbarashe Rusakaniko + Show 3 more

Open Access

https://doi.org/10.1186/s40360-021-00497-8

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Abstract

BackgroundDrug potency is a pharmacological parameter defining dose or concentration of drug required to obtain 50% of the drug’s maximal effect. Pharmacokinetic-pharmacodynamic modelling and simulation allows estimation of potency and evaluate strategies improving treatment outcome. The objective of our study is to determine potency of atazanavir in hair, defined as atazanavir level in hair associated with 50% probability of failing to achieve viral load below 1000 copies/ml among adolescents, and explore the effect of participant specific variables on potency.MethodsA secondary analysis was performed on data from a previous study conducted in HIV-infected adolescents failing 2nd line ART from Harare central hospital, Zimbabwe, between 2015 and 2016. We simulated atazanavir concentrations in hair using NONMEM (version 7.3) ADVAN 13, based on a previously established pharmacokinetic model. Logistic regression methods were used for PKPD analysis. Simulations utilising PKPD model focused on estimation of potency and exploring the effect of covariates.ResultsThe potency of atazanavir in hair was found to be 4.5 ng/mg hair before adjusting for covariate effects. Participants at three months follow-up, reporting adequate adherence, having normal BMI-for-age, and cared for by mature guardians had increased potency of atazanavir in hair of 2.6 ng/mg, however the follow-up event was the only statistically significant factor at 5% level.ConclusionAtazanavir in hair in the range 2.6 to 4.5 ng/mg is associated with above 50% probability of early viral load suppression. Adherence monitoring to adolescents with lower potency of atazanavir is recommended. The effect self-reported adherence level, BMI-for-age, and caregiver status require further evaluation.

Highlights

Drug potency is a pharmacological parameter defining dose or concentration of drug required to obtain 50% of the drug’s maximal effect
Most of the study participants estimated to be 82% were on tenofovir/lamivudine/atazanavir/ritonavir drug combination
The choice of using atazanavir in the model does not have an association with the usefulness of drugs in clinical practise, but merely because they were feasibly available to the authors during the modelling work

Summary

Introduction

Drug potency is a pharmacological parameter defining dose or concentration of drug required to obtain 50% of the drug’s maximal effect. Pharmacokinetic-pharmacodynamic modelling and simulation allows estimation of potency and evaluate strategies improving treatment outcome. The application of exposure-response analysis remains very crucial in testing drug research or development strategies in all phases. The exposure may be the dose or a relevant pharmacokinetic (PK) measure such as drug concentration. The response is referred to as the pharmacodynamic (PD) outcome. If the exposure being used is derived from a PK model, such exposure-response analysis is referred as PKPD modelling. Drug potency is the dose or concentration of a drug required to get 50% of that drug’s maximal effect, expressing the intensity of drug activity. A drug that causes a response to occur at a lower concentration has higher potency and is desirable compared to a drug causing the same response at a higher concentration [1]

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