Methods
Studies. Pharmacokinetic data were pooled from three studies
where oral 40-mg esomeprazole was given. From PIE, day one
concentrations were available from pregnant patients treated with
esomeprazole capsules (Nexium brand).13 Day one and
day five concentrations obtained from healthy, non-pregnant individuals
were included from two studies: those from Hunfeld et al . were
treated with MUPS tablets while those from Helgadóttir et al.were treated with Actavis tablets.14,15 Meal times
differed between the studies: 2 hours post-dose for PIE and Helgadóttiret al . and 5 minutes post-dose for Hunfeld et al . CYP2C19
genotype information was available for the study by Hunfeld et
al .14 In all the studies, esomeprazole concentrations
were quantified using validated LC-MS/MS. For Helgadóttir et al.,esomeprazole concentrations were determined at Actavis pharmaceutical
company in Iceland. For Hunfeld et al. , the methods used for lab
analysis of esomeprazole concentrations have been previously
published,16 and analysis was done at the laboratory
of the Central Hospital Pharmacy, Netherlands. For PIE, esomeprazole
concentrations were determined at the Tygerberg Hospital laboratory, the
details of which have been included in the original
publication.13 The lower limit of quantifications
(LLOQ) were 0.001, 0.0260 mg/l, and 0.00503, PIE, Hunfeld et al .
and Helgadóttir et al ., respectively.13–15
Pharmacokinetic analysis. Population pharmacokinetic analysis
was performed using non-linear mixed-effects software NONMEM (v7.4.3,
Icon®), PsN v4.9.0, Pirana v2.9.8, and R v3.6.1 for data
processing.17 The first-order conditional estimation
method with interaction was used for model runs. Concentrations below
the limit of quantification were handled similarly to the M6 method by
Beal, with additive error inflated by LLOQ/2.18
The clearance and bioavailability after a single dose in non-pregnant
individuals were used as a reference to report the percentage change in
pregnancy or repeated dosing. The pregnancy and the repeated-dosing
effects were then tested as a categorical covariate on clearance and
bioavailability for each genotype subgroup (CYP2C19 extensive and poor
metabolizers). For individuals where genetic information was not
available, a mixture model was used for imputation, as suggested by
Keizer et al .19 We used proportions fixed to
95% and 5%, for extensive and poor metabolisers, respectively, based
on literature.20 Study effects were also tested as
covariates on all absorption parameters to account for differences in
formulation and mealtimes between the studies.
A non-parametric bootstrap (n=500) was run on the final model to obtain
95% confidence intervals (CIs) for the parameter estimates.