(T1230-03-17) Meta-Analysis of the Across-Species Pharmacokinetics of Metronidazole with a Minimal Physiologically-Based Pharmacokinetic Model

Purpose: Metronidazole (MTZ) is frequently used in the treatment of infections caused by certain protozoa and anaerobic bacteria in humans and animals. However, off-label use of nitroimidazoles has become increasingly common. This study evaluated all available published reports on the pharmacokinetics (PK) of MTZ in various species and integrated allometric scaling with a minimal physiologically-based pharmacokinetic model (mPBPK) for a global assessment of common features in absorption and disposition of the drug.

Methods: This mPBPK Allometric Meta-Analysis (MAMA) yielded PK data for MTZ in 11 species (rat, cat, dog, chicken, pigeon, goose, sheep, goat, turkey, horse, and human) from 28 publications. PK profiles were first digitized for noncompartmental analysis (NCA). Physiological parameters (organ weights and blood flow) were obtained from the literature or derived using allometric relationships. The selected mPBPK model had blood (arterial and venous) as a single compartment with lumping of all body tissues (Figure 1) (1). Intravenous (IV) and oral (PO) profiles for 11 species were evaluated separately and then jointly with various shared parameters. The maximum likelihood method was used for nonlinear regression analysis of differential equations using ADAPT 5.

Results: MTZ is a well-studied anti-infective compound that is well-absorbed and highly metabolized, with numerous single-dose IV and oral PK reports in many species. An initial traditional assessment of reported or NCA MTZ clearances (CL) and volumes (V_ss) versus body weights (BW) showed reasonable correlations (R² = 0.9347 and 0.9435) with log-log allometric exponents of 0.9539 and 0.8444. Physiological parameters such as cardiac output (Q_co) were calculated using Q_co = 0.235·BW^0.75 from Brown (2). Organ volumes (V_b) were set as proportions of BW. MTZ is a BCS Class I (high permeability, high solubility) compound, indicating likely perfusion-limited distribution with f_d = 1.0 (3). One suitable IV and oral PK profile for each species was selected for a balanced assessment across species. The mPBPK model adequately captured the individual IV PK profiles (Figure 2) when using species-specific CL values and a generalized tissue partition coefficient (K_p) of 0.706 (CV 3.5%). The IV and PO profiles were then best fitted jointly with shared physiological parameters and the first-order absorption rate constant (k_a), and species-specific values of bioavailability (F), K_p, and CL for 9 species. Joint fittings were excellent, and values of F ranged from 32% for rat and up to about 80% for many others. Estimations of K_p ranged from 0.55 to 1.44 (mean of 0.86).

Conclusion: PK profiles of MTZ for 11 species were successfully evaluated using the mPBPK model integrated with allometric components. The mPBPK model with one tissue compartment precisely captured the bi-exponential disposition of MTZ for all species. Literature-reported CL values were largely confirmed that were roughly, but not exactly, related by a power function of BW. The distribution kinetics of MTZ were generally conserved across species, but with moderate variability. This analysis demonstrates the utility of MAMA in gaining a generalized perspective on the properties of an important drug across numerous species.

References: 1. Cao Y, Jusko WJ. Applications of minimal physiologically-based pharmacokinetic models. Journal of Pharmacokinetics and Pharmacodynamics. 2012;39:711-23.
2. Brown RP, Delp MD, Lindstedt SL, Rhomberg LR, Beliles RP. Physiological parameter values for physiologically based pharmacokinetic models. Toxicology and Industrial Health. 1997;13(4):407-84.
3. Jeong Y-S, Jusko WJ. Meta-assessment of metformin absorption and disposition pharmacokinetics in nine species. Pharmaceuticals. 2021;14(6):545.

Acknowledgements: This study was supported by The National Institute of General Medical Sciences (R35 GM131800).

Figure 1. Structure of the minimal physiologically-based pharmacokinetic model with one tissue compartment. Symbols are defined as: the amount of drug in depot compartment (Aa), the first-order absorption rate constant (ka), bioavailability (F), plasma (Cp) and tissue (Ct) concentrations, blood (Vb) and tissue (Vt) volumes, cardiac output (QCO), fraction of QCO for tissue compartment (fd), tissue-to-plasma partition coefficient (Kp), and systemic clearance (CLp).

Figure 2. The minimal physiologically-based pharmacokinetic model joint fitting of IV PK data from 11 species.