Table 2.
Parameter estimates of the integrated mother–neonate population PK model of raltegravir
| Parameter | Unit | Estimate | CI95 | Bootstrap result | |||
|---|---|---|---|---|---|---|---|
| Low | High | Median | P2.5 | P97.5 | |||
| Neonate (raltegravir unexposed and raltegravir exposed) | |||||||
| V2 | L | 7.04 | 5.07 | 9.75 | 7.16 | 4.85 | 9.91 |
| V3 | L | 10.3 | 7.97 | 13.4 | 10.3 | 7.37 | 13.4 |
| CLmax | L/hour | 9.44 | 7.44 | 11.4 | 9.34 | 7.44 | 11.8 |
| Q | L/hour | 0.786 | 0.559 | 1.11 | 0.8 | 0.538 | 1.2 |
| KAmax | 1/hour | 0.43 | 0.306 | 0.555 | 0.452 | 0.315 | 0.875 |
| F4 (fixed) | – | 1 | – | – | 11.3 | 7.38 | 15.9 |
| CLbase | L/hour | 0 | – | – | 0.0876 | 0.0216 | 0.247 |
| CLtau | 1/year | 11.3 | 7.56 | 15.1 | 60.8 | 6.7 | 135 |
| Kabase | 1/hour | 0.0915 | 0.0343 | 0.245 | 0.314 | 0.132 | 0.483 |
| Katau | 1/year | 63.2 | 1.4 | 125 | 0.178 | 0.0802 | 0.291 |
| IIV on CL | – | 0.33 | 0.108 | 0.552 | 7.16 | 4.85 | 9.91 |
| IIV on KA | – | 0.196 | 0.103 | 0.289 | 10.3 | 7.37 | 13.4 |
| Mothera | |||||||
| V2 (fixed) | L | 3.52 | – | – | |||
| V3 (fixed) | L | 27 | – | – | |||
| CL (fixed) | L/hour | 9.73 | – | – | |||
| Q (fixed) | L/hour | 0.866 | – | – | |||
| KA | 1/hour | 0.175 | 0.0888 | 0.261 | 0.178 | 0.0576 | 0.42 |
| F | – | 0.517 | 0.404 | 0.631 | 0.527 | 0.381 | 0.734 |
| IIV on F | – | 0.311 | 0.0834 | 0.538 | 0.283 | 0.101 | 1.01 |
| Residual error | |||||||
| RUV‐prop | – | 0.54 | 0.498 | 0.582 | 0.536 | 0.489 | 0.577 |
| RUV‐add | nM | 11.9 | 9.11 | 14.7 | 11.6 | 9.95 | 40.9 |
| Shrinkage | |||||||
| IIV CL (neonate) | 9.3% | ||||||
| IIV KA (neonate) | 24.0% | ||||||
| IIV F (mother) | 51.4% | ||||||
| ε | 5.6% | ||||||
Typical values of clearances and volumes refer to a subject weighing 25 kg.
CI95 low, lower limit of the 95% confidence interval; CI95 high, upper limit of the 95% confidence interval; CLbase, typical value of apparent clearance at birth; CLmax, maximum increase in apparent clearance from CLbase; CLtau, first‐order rate constant for the age‐related changes in apparent clearance; F, oral bioavailability mother relative to granules for suspension formulation25; F4, oral bioavailability neonate (after birth); IIV, interindividual variability; KAbase, typical value of absorption rate constant at birth; KAmax, maximum increase in absorption rate constant from KAbase; KAtau, first‐order rate constant for the age‐related changes in absorption rate constant; P2.5, 2.5% percentile; P97.5, 97.5% percentile; PK, pharmacokinetic; Q, typical value of apparent intercompartmental clearance; RUV‐add, additive term of the residual error; RUV‐prop, proportional term of the residual error; V2, typical value of apparent central volume of distribution; V3, typical value of apparent peripheral volume of distribution.
Mother PK component of the integrated model was based on limited information and was used only to inform about the initial raltegravir concentrations in the neonate of each mother at birth.