Papers – PMX Africa

Research Paper: Intracellular Penetration of Atazanavir, Ritonavir and Dolutegravir With Concomitant Rifampicin: A Dose Escalation Study

1 February 2025

The results from this study confirmed that the dose escalation strategy is capable of restoring ATV/r concentrations within the intracellular compartment comparable to those observed before the introduction of rifampicin, providing an important validation to the evidence from the plasma compartment, with pharmacodynamic and clinical implications.

[Research Paper] Culturally appropriate terminologies in health research: a participatory study with pregnant and breastfeeding mothers in Uganda

23 January 2025

Read this paper here The findings highlight the importance of using culturally sensitive language in health research to improve engagement and participation. By adopting community-preferred terms, researchers can avoid confusion and stigma. We offer guidance for future research, advocating for community-driven inclusive language in research involving pregnant and breastfeeding women. Background: The language used in research and health programs is crucial in influencing participation and ensuring the acceptability of programs and the adoption of research outcomes. The use of alienating language may present a barrier for research participants hence the need to identify accurate, respectful, relevant, and acceptable terms for respective study populations. The study explored commonly used terminologies during research involving pregnant and lactating mothers using public engagement and participatory approaches in Uganda.

New paper showcases pharmacometrics transition from capacity development to job creation in Africa

24 December 2024

Pharmacometrics Africa is proud to spotlight the recent review article, Advancing Pharmacometric Capacity in Africa—Transition from Capacity Development Toward Job Creation, published in CPT: Pharmacometrics & Systems Pharmacology.

[Research Paper] Understanding Drug Exposure and Trichuris trichiura Cure Rates: A Pharmacometric Approach for Albendazole-Ivermectin Co-medication in Tanzania and Côte d’Ivoire

29 November 2024

This project was carried out in part by the 2022 APT Fellows as part of the fellowship programme. Abstract Background and Objective Trichuriasis caused by the human whipworm Trichuris trichiura poses a significant public health concern. Albendazole-ivermectin co-medication is currently the most effective treatment. Studies conducted in Tanzania and Côte d’Ivoire unveiled differences in efficacy for albendazole-ivermectin combination therapy in both countries. A pharmacometrics approach was used to assess co-medication and study population effects on the pharmacokinetics of the two main metabolites of albendazole. An exploratory exposure-efficacy analysis was also carried out to investigate relationships between exposure measures and the egg reduction rate. Methods Pharmacokinetic data from studies in Tanzania and Côte d’Ivoire in adolescents (aged 12–19 years) were included in the pharmacometric analysis. Participants received a single dose of either albendazole 400 mg alone or in combination with ivermectin 200 μg/kg. A pharmacometric analysis was performed to investigate the potential effects of the study population and co-administered ivermectin on the apparent clearance of the metabolites of albendazole. Non-linear mixed-effects modeling was conducted with MonolixSuite 2023R1. The pharmacokinetic exposure measures derived from simulations with individual model parameters were used in the exploratory-exposure response analysis. Results Pharmacokinetic profiles were best described by a two-compartment model for albendazole sulfoxide and a one-compartment model for albendazole sulfone, with a transit compartment and linear elimination. While no co-medication effect was found, apparent clearance of albendazole sulfoxide (albendazole sulfone) in the Tanzanian study population was 75% (46%) higher than that in the Côte d’Ivoire study

[Research Paper] Population pharmacokinetic modeling of paired plasma–breast milk lamivudine data for estimation of infant exposure in breastfeeding mother–infant pairs

14 November 2024

Read the entire paper here Abstract: Around 1.2 million women living with HIV give birth annually, majority of whom will breastfeed their infants while receiving antiretroviral therapy (ART). Lamivudine, a component of first‐line ART regimens crosses from maternal plasma to breast milk, with measurable concentrations in some breastfed infants. Wide variability in plasma‐to‐breast milk transfer has been reported within‐ or across studies, probably due to differences in sampling framework. This work sought to characterize the milk‐to‐plasma transfer of lamivudine, quantify inter‐patient variability and associated factors, and predict exposure of a breastfed infant. We explored data from an observational pharmacokinetic study that included 35 Ugandan mothers and their infants. Mothers received lamivudine doses of 150 mg twice daily or 300 mg once daily as part of their antiretroviral regimen. Pharmacokinetic sampling was undertaken across two visits approximately 8 weeks apart, providing 248 maternal plasma, 256 breast milk‐, and 151 infant blood concentrations, measured across a 24‐h sampling interval. A one‐compartmental model best described the plasma disposition of lamivudine, with first‐order absorption, interindividual variability on clearance and volume of distribution, and a proportional residual error model. A lag in time of plasma‐to‐breast milk drug accumulation was described using an effect compartment model with a milk‐to‐plasma ratio of 1.77. An estimated daily infant dose of 179.3 μg/kg (range: 125.8, 282.3) closely predicted the observed infant steady‐state concentrations and translated into 3.34% (2.13, 7.20) and 3.35% (1.10, 7.15) of the standard daily maternal dose in visits 1 and 2, respectively. The established modeling framework can be extended to

[Research Paper] Using PBPK modeling to supplement clinical data and support the safe and effective use of dolutegravir in pregnant and lactating women

13 November 2024

Read the paper here Optimal dosing in pregnant and lactating women requires an understanding of the pharmacokinetics in the mother, fetus, and breastfed infant. Physiologically-based pharmacokinetic (PBPK) modeling can be used to simulate untested scenarios. A PBPK model for the antiretroviral dolutegravir was verified using reported exposures in non-pregnant healthy volunteers, pregnant women, and the umbilical cord, lactating mothers, and breastfed neonates. Abstract Optimal dosing in pregnant and lactating women requires an understanding of the pharmacokinetics in the mother, fetus, and breastfed infant. Physiologically‐based pharmacokinetic (PBPK) modeling can be used to simulate untested scenarios and hence supplement clinical data to support dosing decisions. A PBPK model for the antiretroviral dolutegravir (mainly metabolized by UGT1A1) was verified using reported exposures in non‐pregnant healthy volunteers, pregnant women, and the umbilical cord, lactating mothers, and breastfed neonates. The model was then applied to predict the impact of UGT1A1 phenotypes in extensive (EM), poor (PM), and ultra‐rapid metabolizers (UM). The predicted dolutegravir maternal plasma and umbilical cord AUC in UGT1A1 PMs was 1.6‐fold higher than in EMs. The predicted dolutegravir maternal plasma and umbilical cord AUC in UGT1A1 UMs mothers was 1.3‐fold lower than in EMs. The predicted mean systemic and umbilical vein concentrations were in excess of the dolutegravir IC90 at 17, 28, and 40 gestational weeks, regardless of UGT1A1 phenotype, indicating that the standard dose of dolutegravir (50 mg q.d., fed state) is generally appropriate in late pregnancy, across UGT1A1 phenotypes. Applying the model in breastfed infants, a 1.5‐, 1.7‐, and 2.2‐fold higher exposure

Research Paper: Interim analysis, a tool to enhance efficiency of pharmacokinetic studies: Pharmacokinetics of rifampicin in lactating mother-infant pairs

13 November 2024

Read this commentary here The objectives of this interim analysis were to define the transfer of rifampicin to a breastfed infant and to determine the area under the concentration-time curve of rifampicin in maternal plasma, breastmilk and infant plasma. Performing this interim analysis enabled us to substantiate whether prior assumptions we made on several study design issues including patient sample size and pharmacokinetic sampling times held and whether we needed to amend our protocol or not. Abstract Pharmacokinetic studies are important for understanding drug disposition in the human body. However, pregnant and lactating women are often excluded from primary pharmacokinetic studies and as such there is often limited dosing information regarding drug use in pregnant and/or lactating women. The objectives of this interim analysis were to define the transfer of rifampicin to a breastfed infant and to determine the area under the concentration–time curve of rifampicin in maternal plasma, breastmilk and infant plasma. Performing this interim analysis enabled us to substantiate whether prior assumptions we made on several study design issues including patient sample size and pharmacokinetic sampling times held and whether we needed to amend our protocol or not. We enrolled lactating mothers on treatment for tuberculosis with their breastfeeding infants (below 12 months of age), performed intensive pharmacokinetic sampling (0–24 h post‐dose) on plasma samples from both the mother, infant(s) and breastmilk samples from the mother on two separate occasions (once during the initiation phase and another during the continuation phase of tuberculosis treatment). The initial study design, including sampling

[Editorial] What can pharmacokinetic modelling do for you? Rational design and interpretation of clinical studies

8 November 2024

Read this editorial here Editorial for themed issue of the British Journal of Clinical Pharmacology. By drawing together key exemplars illustrating the use of several pharmacometric approaches, we aim to showcase this methodology and excite the reader that the time is coming when all individuals are able to access individualized guidance on the safest, most effective use of medications.

[Research Paper] Physiologically based pharmacokinetic modeling of drug-drug interactions between ritonavir-boosted atazanavir and rifampicin in pregnancy

8 November 2024

Read this paper here Abstract: Ritonavir-boosted atazanavir (ATV/r) and rifampicin are mainstays of second-line antiretroviral and multiple anti-TB regimens, respectively. Rifampicin induces CYP3A4, a major enzyme involved in atazanavir metabolism, causing a drug–drug interaction (DDI) which might be exaggerated in pregnancy. Having demonstrated that increasing the dose of ATV/r from once daily (OD) to twice daily (BD) in non-pregnant adults can safely overcome this DDI, we developed a pregnancy physiologically based pharmacokinetic (PBPK) model to explore the impact of pregnancy. Predicted pharmacokinetic parameters were validated with separate clinical datasets of ATV/r alone (NCT03923231) and rifampicin alone in pregnant women. The pregnancy model was considered validated when the absolute average fold error (AAFE) for Ctrough and AUC0-24 of both drugs were <2 when comparing predicted vs. observed data. Thereafter, predicted atazanavir Ctrough was compared against its protein-adjusted IC90 (14 ng/mL) when simulating the co-administration of ATV/r 300/100 mg OD and rifampicin 600 mg OD. Pregnancy was predicted to increase the rifampicin DDI effect on atazanavir. For the dosing regimens of ATV/r 300/100 mg OD, ATV/r 300/200 mg OD, and ATV/r 300/100 mg BD (all with rifampicin 600 mg OD), predicted atazanavir Ctrough was above 14 ng/mL in 29%, 71%, and 100%; and 32%, 73% and 100% of the population in second and third trimesters, respectively. Thus, PBPK modeling suggests ATV/r 300/100 mg BD could maintain antiviral efficacy when co-administered with rifampicin 600 mg OD in pregnancy. Clinical studies are warranted to confirm safety and efficacy in pregnancy.

Category: Papers

Research Paper: Intracellular Penetration of Atazanavir, Ritonavir and Dolutegravir With Concomitant Rifampicin: A Dose Escalation Study

[Research Paper] Culturally appropriate terminologies in health research: a participatory study with pregnant and breastfeeding mothers in Uganda

New paper showcases pharmacometrics transition from capacity development to job creation in Africa

[Research Paper] Population pharmacokinetic modeling of paired plasma–breast milk lamivudine data for estimation of infant exposure in breastfeeding mother–infant pairs

[Research Paper] Using PBPK modeling to supplement clinical data and support the safe and effective use of dolutegravir in pregnant and lactating women

Research Paper: Interim analysis, a tool to enhance efficiency of pharmacokinetic studies: Pharmacokinetics of rifampicin in lactating mother-infant pairs

[Editorial] What can pharmacokinetic modelling do for you? Rational design and interpretation of clinical studies

[Research Paper] Physiologically based pharmacokinetic modeling of drug-drug interactions between ritonavir-boosted atazanavir and rifampicin in pregnancy

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