A Comparative Analysis of Physiologically Based Pharmacokinetic Models for Human Immunodeficiency Virus and Tuberculosis Infections

Abstract

Physiologically based pharmacokinetic (PBPK) models have gained in popularity in the last decade in both drug development and regulatory science. PBPK models differ from classical pharmacokinetic models in that they include specific compartments for tissues involved in exposure, toxicity, biotransformation, and clearance processes connected by blood flow. This study aimed to address the gaps between the mathematics and pharmacology framework observed in the literature. These gaps included nonconserved systems of equations and compartment concentration that were not biologically relatable to the tissues of interest. The resulting system of nonlinear differential equations is solved numerically with various methods for benchmarking and comparison. Furthermore, a sensitivity analysis of all parameters were conducted to elucidate the critical parameters of the model. The resulting model was fit to clinical data as a performance benchmark. The clinical data captured the second line of antiretroviral treatment, lopinavir and ritonavir. The model and clinical data correlate well for coadministration of lopinavir/ritonavir with rifampin. Drug-drug interaction was captured between lopinavir and rifampin. This article provides conclusions about the suitability of physiologically based pharmacokinetic models for the prediction of drug-drug interaction and antiretroviral and anti-TB pharmacokinetics.

Keywords: pharmacodynamics; pharmacokinetics.

FIG 1

Antiretroviral and anti-tuberculosis treatment physiologically based pharmacokinetic (PBPK) structure.

FIG 2

Rifampin in humans, capturing large concentration compartments.

FIG 3

Rifampin in humans.

FIG 4

Rifampin in mice, capturing large concentration compartments.

FIG 5

Rifampin in mice.

FIG 6

Rifampin in mice, capturing low concentration compartments.

FIG 7

Efavirenz in humans, capturing large concentration compartments.

FIG 8

Efavirenz in humans.

FIG 9

Efavirenz in humans, capturing low concentration compartments.

FIG 10

Efavirenz in mice, capturing large concentration compartments.

FIG 11

Efavirenz in mice.

FIG 12

Efavirenz in mice, capturing low concentration compartments.

FIG 13

Sensitivity of different parameters values of fractional renal clearance, $F_R$. C_L, liver concentration; C_LU, lung concentration; C_B, bone concentration; C_K, kidney concentration; C_BR, brain concentration; C_H, heart concentration; C_M, muscle concentration; C_SK, skin concentration; C_CR, carcass concentration.

FIG 14

Sensitivity of total blood clearance, $\delta$.

FIG 15

Mean ± SD concentration-time profile standard dose regimen and coadministration dose regimen.

FIG 16

Standard dose regimen and coadministration dose regimen.

FIG 17

Ritonavir single dose and coadministration dose of ritonavir and rifampin.

FIG 18

Standard dose regimen and coadministration dose regimen.

FIG A1

Sensitivity of the bone volume, $V_B$.

FIG A2

Sensitivity of the carcass blood flow, $Q_{\mathit{CR}}$.

FIG A3

Sensitivity of the hepatic artery blood flow, $Q_{\mathit{LA}}$.

FIG A4

Sensitivity of gut lumen transit rate $k_F$. C_L, liver concentration; C_GL, gut lumen concentration; C_G, gut concentration.

FIG A5

Sensitivity of maximum rate of metabolism, $V_{\mathit{max}}$. C_LU, lung concentration; C_B, bone concentration; C_K, kidney concentration; C_BR, brain concentration; C_H, heart concentration; C_M, muscle concentration; C_SK, skin concentration; C_CR, carcass concentration; C_GL, gut lumen concentration; C_G, gut concentration; C_ST Stomach concentration; C_A, arterial concentration; C_v, venous concentration.

FIG A6

Sensitivity of venous blood volume, $V_v$.

FIG A7

Sensitivity of lung volume, $V_{\mathit{LU}}$.

FIG A8

Sensitivity of fractional drug absorption, $F_a$.

FIG A9

Sensitivity of the drug absorption rate, $k_{\mathit{ST}}$.

FIG A10

Sensitivity of the brain blood flow, $Q_{\mathit{BR}}$.

FIG A11

Sensitivity of the liver volume, $V_L$.

FIG A12

Sensitivity of the spleen volume, $V_S$.

FIG A13

Sensitivity of the stomach volume, $V_{\mathit{ST}}$.