Table 2.
Final Parameter Estimates for the Rifapentine Population Pharmacokinetic Model
| Parameter | Population Estimate |
Interindividual Variability |
||
|---|---|---|---|---|
| Value (%RSE) | 95% CI* | %CV (%RSE) | 95% CI* | |
| CL/F, L/h | 1.11 (1.92) | 0.952–1.48 | 24.3 (9.34) | 12.8–28.0 |
| V/F, L | 36.7 (1.99) | 28.5–40.9 | 17.6 (17.7) | 10.5–24.0 |
| MTT, h | 1.94 (2.97) | 1.83–2.04 | — | — |
| NN | 2.15 (5.44) | 1.66–2.70 | — | — |
| Bioavailability | 100 fixed | — | 29.8 (10.8) | 21.5–34.6 |
| Fixed effects on bioavailability† | ||||
| Dose | 0.0167 (5.30) | 0.00343–0.0287 | — | — |
| HIV infection | 0.729 (6.26) | 0.584–0.815 | — | — |
| High-fat meal | 1.49 (3.05) | 1.37–1.64 | — | — |
| Fasting | 0.731 (5.51) | 0.546–0.776 | — | — |
| kENZ, h−1‡§ | 0.00587 (32.1) | 0.00291–0.0135 | — | — |
| Emax, %‡ | 73.0 (25.2) | 51.0–116 | — | — |
| EC50, mg/L‡ | 4.27 (39.8) | 1.80–6.57 | — | — |
| γ | 10 fixed | — | — | — |
| Residual error of rifapentine | 0.577 (4.13) | 0.573–0.699 | — | — |
| CLm/fm, L/h | 3.11 (12.2) | 1.89–6.26 | 40.0 (6.69) | 34.2–44.6 |
| Vm/fm, L | 2.15 (7.07) | 1.67–3.15 | — | — |
| fm,dose‖ | 0.0185 (3.56) | 0.0004–0.0266 | — | — |
| HIV effect on CLm/fm | 1.36 (9.85) | — | — | — |
| Residual error of metabolite | 0.631 (5.59) | 0.560–0.695 | — | — |
Definition of abbreviations: CI = confidence interval; CL/F = apparent clearance; CLm/fm = apparent metabolite clearance; CV = coefficient of variation; EC50 = concentration at which effect is 50% of Emax; Emax = maximum effect; F = bioavailability; fm = fraction metabolized; fm,dose = dose-dependent reduction in fm; γ = steepness for Emax equation; kENZ = enzyme production rate; MTT = mean transit time; NN = number of transit compartments; RSE = relative SE; V/F = apparent volume of distribution; Vm/fm = apparent metabolite volume of distribution.
CIs were based on 926 (out of 1,000) successful bootstrap runs for rifapentine model and 999 (out of 1,000) successful bootstrap runs for metabolite model.
Fixed effects on F were relative to HIV-negative individuals receiving 300 mg of rifapentine with a low-fat meal, where F = 1 for each reference condition. Relative bioavailability is calculated as F = Fdose × Fhiv × Fhigh-fat × Ffasting, where Fdose is the relative reduction in bioavailability per 100 mg above 300 mg [equal to 1 − estimate × (dose/100 mg)], Fhiv is the relative bioavailability in HIV-positive individuals, Fhigh-fat is the relative bioavailability with a high-fat meal (vs. low-fat meal), and Ffasting is the relative bioavailability with fasting (vs. low-fat meal).
Autoinduction parameters were estimated on the basis of the analysis data set alone.
Translates to an enzyme turnover half-life of 118 hours.
The fm is a function of dose, where fm = 1 − fm,dose × (dose/100 mg).