TABLE 2.
Parameter estimates from the final combined model for lopinavir and ritonavir in HIV-infected children with and without MDR-TB treatmenta
| Parameter | Lopinavir estimate (%RSE) | Ritonavir estimate (%RSE) | Lopinavir-ritonavir interaction estimate (%RSE) |
|---|---|---|---|
| CL (liters/h)b | 2.14c (3) | 16.8 (11) | |
| V (liters)b | 26.4 (16) | 74.1 (12) | |
| ka (1/h) | 0.424d (36) | 0.281d (4) | |
| F (unitless) | 1 (fixed) | 1 (fixed) | |
| Additive error (mg/liter) | 0.0039 (fixed)e | 0.00097 (fixed)e | |
| Proportional error (%) | 15 (7) | 29 (7) | |
| Change in CL at night (%) | −29 (3) | −38 (6) | |
| IIV in CL (%CV)f | 50 (19) | 69 (16) | |
| IOV in F (%CV)f | 41 (20) | 64 (15) | |
| IOV in ka (%CV)f | 61 (23) | ||
| Imax (unitless) | 0.82 (fixed)g | ||
| EC50 (mg/liter) | 0.098 (fixed)g | ||
| γ (unitless) | 2.8 (fixed)g | ||
| Correlation for IIV in CL lopinavir-ritonavir (%) | 64 (22) | ||
| Correlation for IOV in F lopinavir-ritonavir (%) | 99 (4) |
Data are for 32 children. RSE, relative standard error; CL, apparent oral clearance; V, apparent volume of distribution; ka, absorption rate constant; F, bioavailability; IIV, interindividual variability; IOV, interoccasion variability; CV, coefficient of variation; Imax, maximum inhibition; EC50, the concentration at which 50% of the maximal inhibitory effect is obtained; γ, the Hill coefficient, or the shape factor of the curve.
Clearance and volume of distribution were estimated using allometric scaling, and the values reported here are for a child of 11 kg.
The value for lopinavir clearance reported here was calculated for a median ritonavir concentration of 0.3 mg/liter to include the inhibitory effect of ritonavir. The model would have otherwise extrapolated a value for lopinavir clearance in the absence of ritonavir, which is not the case, since lopinavir was never administered alone.
A Bayesian prior with values from Zhang et al. (20) was used for the estimation of ka.
The estimate of additive error for lopinavir and ritonavir was not stable and tended to 0, so it was fixed to 20% of the LLOQ for each drug.
IIV and IOV were assumed to have a lognormal distribution, and their magnitudes are reported here as approximate coefficients of variation.
These values were fixed to the values previously reported for a similar population (20) to improve model stability.