Henry Enzama 1, Raphaëlle Lesage 2, Cleo Demeester 2,3, Marco Siccardi 2, Collen Masimirembwa 4, Catriona Waitt 5
1 Makerere University (Kampala, Uganda), 2 ESQlabs GmbH (Saterland, Germany), 3 MPSlabs, ESQlabs GmbH, ( Saterland, Germany), 4 African Institute of Biomedical Science and Technology (AiBST (Harare, Zimbabwe), 5 University of Liverpool (Liverpool, United Kingdom)
Background.
Physiologically based pharmacokinetic (PBPK) models generate exposure predictions from drug-specific parameters interacting with system (population) inputs such as organ volumes, blood flows, plasma protein concentrations, enzyme and transporter abundance, gastrointestinal physiology, hematocrit, and renal function. Most commercial and regulatory PBPK system libraries are parameterized using European and North American datasets (1,2). Given the high genetic diversity, heterogeneous anthropometry, altitude variation, and substantial infectious disease burden across Sub-Saharan Africa, direct transport of default system priors may bias exposure predictions. The objective of this work was to identify African-context anatomical, physiological, biochemical, anthropometric, pharmacogenetic, and inflammation-related evidence and translate these into parameter-ready PBPK inputs and variability distributions.
Methods
A structured PRISMA-informed evidence synthesis (2010–2025) was conducted across PubMed, PMC, and major biomedical publishers. Eligible studies reported extractable quantitative human data from African populations or African-ancestry cohorts relevant to PBPK system inputs. Five predefined domains were evaluated: anatomy and anthropometry, pharmacogenetics, plasma protein binding and biochemical variability, gastrointestinal physiology, and renal function and inflammation-mediated modulation.
Extracted data were mapped to PBPK constructs, including organ-weight distributions, enzyme phenotype fractions, intrinsic clearance scalars, gastric pH time-above-threshold metrics, transit time distributions, hematocrit distributions, glomerular filtration rate (GFR) distributions, and inflammation-linked activity modifiers. Heterogeneity across cohorts was encoded as variability distributions rather than single-point estimates.
Results
Autopsy datasets from KwaZulu-Natal (n=500) reported mean (±SD) liver weight 1376.6 ± 435.4 g and kidney weights 146.7 ± 55.9 g (right) and 154.3 ± 55.8 g (left) (3). In Zambia (n=114), male liver weight was 1285.3 ± 270.1 g and female 1367.9 ± 357.2 g, with consistent sex-related differences across organ systems (4). Organ mass correlated strongly with body weight, supporting anthropometry-driven scaling rather than fixed ethnicity-based assumptions (5).
Ethiopian community cohorts reported hematocrit reference intervals spanning 40–58% with significant sex differences (P<0.001) (6). Highland residents at 3530 m exhibited mean hemoglobin 15.9 g/dL (males) and 15.0 g/dL (females) with preserved oxygen saturation 95.3% (7), indicating moderate altitude adaptation relevant for blood-to-plasma partition assumptions.
Pharmacogenetic evidence demonstrated substantial regional heterogeneity. CYP3A51 allele frequencies ranged from 4% to 81% across African cohorts, corresponding to approximately 43% expresser prevalence overall (8). CYP3A5 expressers showed lower dose-normalized tacrolimus exposure, supporting mixture-distribution implementation (9). In Ugandan adults, the CYP2B66/*6 genotype was associated with significantly elevated efavirenz exposure, with pharmacogenetic modeling supporting dose reduction to 300 mg in homozygotes (10). A Cameroonian cohort reported CYP2B6 516T allele frequency of 55% (11), highlighting intra-continental variability. Genome analyses reported CYP2C19 allele frequencies of *1 (51%), *2 (17%), and *17 (22%) (12). For SLCO1B1 rs4149056, allele frequencies below 3–6% were reported in several African cohorts (13,14), although transporter functional scalars validated in African pharmacokinetic datasets remain limited (15).
Biochemical variability was consistently observed across health states. Ghanaian reference interval studies reported albumin distributions of approximately 35–50 g/L but emphasized locally derived intervals (16). South African HIV-positive postpartum women had lower albumin compared with HIV-negative controls (17). α1-acid glycoprotein (AGP) was markedly elevated in Tanzanian pulmonary tuberculosis patients (18) and Malawian children with falciparum malaria, where elevation persisted beyond acute infection (19). Meta-analytic evidence indicates acute inflammation reduces CYP3A activity by approximately 30–60% (20), supporting inflammation-dependent intrinsic clearance scalars.
Gastrointestinal physiology data demonstrated measurable diurnal variability. In rural South African adults, 24-hour intragastric monitoring showed mean gastric pH 2.84, nocturnal mean 3.7, and median 136.4 minutes spent at pH ≥4 overnight, with near-universal nocturnal alkalinization (21). In Côte d’Ivoire, total colonic transit time was 34.9 ± 15.1 hours with an upper reference limit of 65 hours (22). Nigerian cohorts reported fasting gallbladder volumes of 24.2 ± 8.4 cm³ and 19.8 ± 9.6 cm³ in independent populations (23,24), demonstrating between-cohort variability relevant for bile-mediated dissolution assumptions.
Multicenter iohexol-measured GFR across Malawi, Uganda, and South Africa ranged 92–104 mL/min/1.73 m², with 12–18% of adults below 60 mL/min/1.73 m² (25). Race-adjusted CKD-EPI equations overestimated measured GFR by approximately 8–15 mL/min/1.73 m², whereas race-neutral equations improved concordance (25,26), supporting race-neutral renal clearance scaling.
Conclusions.
African-context PBPK modeling leverages pharmacogene mixtures, stratified plasma proteins, gastric pH cycles, regional distributions, renal scaling, and inflammation modifiers. Despite gaps in transporter scalars, luminal volumes, and inflammation–PK datasets, structured integration of African variability strengthens mechanistic contextualization, predictive accuracy, regulatory credibility, and pharmacoequity in drug development.
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Reference: PAGE 34 (2026) Abstr 12243 [www.page-meeting.org/?abstract=12243]
Poster: Drug/Disease Modelling - Absorption & PBPK