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This study investigated the effect of delayed or missed doses on the pharmacokinetics (PK) of lamotrigine (LTG) in children with epilepsy and established remedial dosing recommendations for nonadherent patients. The Monte Carlo simulation based on a published LTG population PK model was used to assess the effect of different scenarios of nonadherence and the subsequently administered remedial regimens. The following three remedial approaches were investigated for each delayed dose: A) A partial dose was administered immediately, and the regular dose was administered at the next scheduled time. B) The delayed dose was administered immediately, followed by a partial dose at the next scheduled time. C) The delayed and partial doses were coadministered immediately, the next scheduled dose was skipped, and the regular dosing was resumed at the subsequent scheduled time. The most appropriate remedial regimen was that with the shortest deviation time from the individual therapeutic window. The effect of nonadherence on PK was dependent on the delay duration and daily dose, and the recommended remedial dose was related to the delay duration and concomitant antiepileptic drugs. Remedial dosing strategies A and B were almost equivalent, whereas C showed a larger PK deviation time. If one dose was missed, double doses were not recommended for the next scheduled time. Simulations provide quantitative insight into the remedial regimens for nonadherent patients, and clinicians should select the optimal regimen based on the status of patients. Three remedial strategies identified for a 12-year-old and 40-kg patient administered lamotrigine on 125 mg q12h regimen without an inducer or inhibitor when dose was delayed by 10 h. The dark pink shadow represents the distribution of the 5th–95th percentiles of the simulated concentrations in 90% of the virtual subjects, and the light pink shadows represent the distribution of the simulated concentrations outside the 5th–95th percentiles in the remaining 10% virtual subjects. Red solid line represents median of the simulated concentrations and dotted lines represent 0.5th and 99.5th percentiles of the simulated concentrations, respectively. Black dotted lines represent the individual therapeutic range (2.4–16.8 mg/L). Black solid line represents the deviation time. Unlabelled Image • Monte Carlo simulation was used to develop remedial regimens of nonadherence. • The remedial regimens were dependent on the delayed time and comedications. • Clinicians could select the optimal remedial strategy for individual patients. [ABSTRACT FROM AUTHOR]

Tacrolimus is used clinically for the long-term treatment of antirejection of transplanted organs in liver and kidney transplant recipients, although dose optimization is poorly managed. The aim of this study was to examine the association between tacrolimus pharmacokinetic variability and CYP3A4 and CYP3A5 genotypes by a population pharmacokinetic analysis based on routine drug monitoring data in adult renal transplant recipients.Trough tacrolimus concentrations were obtained from 161 adult kidney transplant recipients after transplantation. The population pharmacokinetic analysis was carried out using the nonlinear mixed-effect modeling software NONMEM version 7.2. The CYP3A4∗1G and CYP3A5∗3 genetic polymorphisms from the patients studied were determined by direct sequencing using a validated automated genetic analyzer.A one-compartment model with first-order absorption and elimination adequately described the pharmacokinetics of tacrolimus. Covariates including CYP3A5∗3 and CYP3A4∗1G alleles and hematocrit were retained in the final model. The apparent clearance of tacrolimus was about two-fold higher in kidney transplant patients with higher enzymatic activity of CYP3A5∗1 and CYP3A4∗1G (with the CYP3A5∗1/∗1 or ∗1/∗3 and CYP3A4∗1/∗1G or CYP3A4∗1G/∗1G) compared with those with lower enzymatic activity (CYP3A5∗3/∗3 and CYP3A4∗1/∗1).This is the first study to extensively determine the effect of CYP3A4∗1G and CYP3A5∗3 genetic polymorphisms and hematocrit value on tacrolimus pharmacokinetics in Chinese renal transplant recipients. The findings suggest that CYP3A5∗3 and CYP3A4∗1G polymorphisms and hematocrit are determinant factors in the apparent clearance of tacrolimus. The initial dose design is mainly based on CYP3A5 and CYP3A4 genotypes as well as hematocrit. This result may also be useful for maintenance tacrolimus dose optimization and may help to avoid fluctuating tacrolimus levels and improve the efficacy and tolerability of tacrolimus in kidney transplant recipients. [ABSTRACT FROM AUTHOR]