Parameter
Typical Value (95% CI)a
Parameter Variability, %CVc
Clearance extensive metabolizers (L/h)b 24.3 (20.5, 29.3) BSV: 23.1 (15.2, 32.9)
Clearance poor metabolizers (L/h)b 7.87 (6.04, 9.75) BSV: 23.1 (15.2, 32.9)
Central volume of distribution (L)b 14.4 (8.70, 20.3)
Intercompartmental clearance (L/h)b 6.47 (2.80, 11.3)
Peripheral volume of distribution (L)b 7.71 (5.78, 10.5)
Relative bioavailability () 1 Fixed BOV: 23.1 (15.2, 29.9)
Absorption rate constant (1/h) 4.80 (2.89, 6.39) BOV: 485 (211, 916)
Mean transit time (h) 1.75 (1.54, 1.94) BOV: 38.8 (29.1, 48.5)
Number of transit compartments 10 Fixedd
Covariatese Covariatese Covariatese
Change in clearance on day five for non-pregnant extensive metabolizers (%)* -54.9 (-63.5, -48.2)
Change in bioavailability on day five for non-pregnant (%)* +33.0 (10.0, 52.0)
Change in clearance on day one for pregnant (%)* -42.2 (-61.6, -14.9)
Change in mean transit time for PIE (%)* -71.9 (-79.3, -58.2)
Change in mean transit time for Hunfeld et al. (%)* -43.1 (-68.7, -30.0)
Residual unexplained variability Residual unexplained variability Residual unexplained variability
Proportional error (%) 36.7 (32.7, 40.5)
Additive error (mg/L) 20% of LLOQf
a95% confidence intervals obtained by non-parametric bootstrap (n=500) bAllometric scaling with total body weight for a reference individual of 70 kg cBetween-subject (BSV) and between-occasion variability (BOV) were obtained using the formula \(\text{sqrt}(\exp\left(OM^{2}\right)-1)\) and reported as approximate %CV dThe number of transit compartments was fixed to 10 to make parameter estimates more stable eStudy effect was tested on parameters with day one data from healthy, non-pregnant participants as reference group *Reference group is day one non-pregnant (non-pregnant group after single dose) fLower limit of quantification (LLOQ) (mg/L) was study-specific: 0.001 for PIE, 0.0260 for Hunfeld et al., and 0.00503 for Helgadóttir et al. a95% confidence intervals obtained by non-parametric bootstrap (n=500) bAllometric scaling with total body weight for a reference individual of 70 kg cBetween-subject (BSV) and between-occasion variability (BOV) were obtained using the formula \(\text{sqrt}(\exp\left(OM^{2}\right)-1)\) and reported as approximate %CV dThe number of transit compartments was fixed to 10 to make parameter estimates more stable eStudy effect was tested on parameters with day one data from healthy, non-pregnant participants as reference group *Reference group is day one non-pregnant (non-pregnant group after single dose) fLower limit of quantification (LLOQ) (mg/L) was study-specific: 0.001 for PIE, 0.0260 for Hunfeld et al., and 0.00503 for Helgadóttir et al. a95% confidence intervals obtained by non-parametric bootstrap (n=500) bAllometric scaling with total body weight for a reference individual of 70 kg cBetween-subject (BSV) and between-occasion variability (BOV) were obtained using the formula \(\text{sqrt}(\exp\left(OM^{2}\right)-1)\) and reported as approximate %CV dThe number of transit compartments was fixed to 10 to make parameter estimates more stable eStudy effect was tested on parameters with day one data from healthy, non-pregnant participants as reference group *Reference group is day one non-pregnant (non-pregnant group after single dose) fLower limit of quantification (LLOQ) (mg/L) was study-specific: 0.001 for PIE, 0.0260 for Hunfeld et al., and 0.00503 for Helgadóttir et al.