Simcyp Ltd a Certara company Sheffield UK

Simcyp Ltd a Certara company Sheffield UK

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Zhou W.,Astrazeneca | Humphries H.,Simcyp A Certara Company Sheffield UK | Neuhoff S.,Simcyp A Certara Company Sheffield UK | Gardner I.,Simcyp A Certara Company Sheffield UK | And 3 more authors.
Biopharmaceutics and Drug Disposition | Year: 2017

Itopride, a substrate of FMO3, has been used for the symptomatic treatment of various gastrointestinal disorders. Physiologically based pharmacokinetic (PBPK) modeling was applied to evaluate the impact of FMO3 polymorphism on itopride pharmacokinetics (PK). The Asian populations within the Simcyp simulator were updated to incorporate information on the frequency, activity and abundance of FMO3 enzyme with different phenotypes. A meta-analysis of relative enzyme activities suggested that FMO3 activity in subjects with homozygous Glu158Lys and Glu308Gly mutations (Lys158 and Gly308) in both alleles is ~47% lower than those carrying two wild-type FMO3 alleles. Individuals with homozygous Lys158 and Gly308 mutations account for about 5% of the total population in Asian populations. A CLint of 9 μl/min/pmol was optimised for itopride via a retrograde approach as human liver microsomal results would under-predict its clearance by ~7.9-fold. The developed itopride PBPK model was first verified with three additional clinical studies in Korean and Japanese subjects resulting in a predicted clearance of 52 to 69 l/h, which was comparable to those observed (55 to 88 l/h). The model was then applied to predict plasma concentration-time profiles of itopride in Chinese subjects with wild type or homozygous Lys158 and Gly308 FMO3 genotypes. The ratios of predicted to observed AUC of itopride in subjects with each genotype were 1.23 and 0.94, respectively. In addition, the results also suggested that for FMO3 metabolised drugs with a safety margin of 2 or more, proactive genotyping FMO3 to exclude subjects with homozygous Lys158/Gly308 alleles may not be necessary. © 2017 John Wiley & Sons, Ltd.


Bonner J.J.,Cancer Research UK Research Institute | Vajjah P.,UCB Celltech Slough UK | Abduljalil K.,Simcyp Ltd a Certara company Sheffield UK | Jamei M.,Simcyp Ltd a Certara company Sheffield UK | And 3 more authors.
Biopharmaceutics and Drug Disposition | Year: 2015

Purpose. Gastric emptying (GE) is often reported to be slower and more irregular in premature neonates than in older children and adults. The aim of this study was to investigate the impact of age and other covariates on the rate of GE. Methods. The effect of age on the mean gastric residence times (MGRT) of liquid and solid food was assessed by analysing 49 published studies of 1457 individuals, aged from 28weeks gestation to adults. The data were modelled using the nonlinear mixed-effects approach within NONMEM version 7.2 (ICON, Dublin, Ireland), with evaluation of postnatal age, gestational age and meal type as covariates. A double Weibull function was selected as a suitable model since it could account for the typical biphasic nature of GE. Results. Age was not a significant covariate for GE but meal type was. Aqueous solutions were associated with the fastest emptying time (mean simulated gastric residence time of 45min) and solid food was associated with the slowest (98min). Conclusions. These findings challenge the assertion that GE is different in neonates, as compared with older children and adults due to age, and they reinforce the significance of food type in modulating GE. © 2015 John Wiley & Sons, Ltd.

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