Physiologically‐based pharmacokinetics of ziprasidone in pregnant women

Abstract

Aims: Pregnancy is associated with physiological changes that alter the pharmacokinetics (PK) of drugs. The aim of this study was to predict the PK of ziprasidone in pregnant women.Methods: A full physiologically-based pharmacokinetic (PBPK) model of ziprasidone was developed and validated for the non-pregnant population (healthy adults, paediatrics, geriatrics), and this was extended to the pregnant state to assess the change in PK profile of ziprasidone throughout pregnancy.Results: The PBPK model successfully predicted the ziprasidone disposition in healthy adult volunteers, wherein the predicted and observed AUC, C max and t max were within the fold-difference of 0.94-1.09, 0.89-1.40 and 0.80-1.08, respectively.The paediatric and geriatric population, also showed predicted AUC, C max and t max within a two-fold range of the observed values. The simulated exposure in pregnant women using a p-PBPK model showed no significant difference when compared to non-pregnant women.Conclusions: The PBPK model predicted the impact of physiological changes during pregnancy on PK and exposure of ziprasidone, suggesting that dose adjustment is not necessary in this special population. KEYWORDS PBPK, pregnancy, ziprasidone1 | INTRODUCTION Nearly one in five US adults lives with someone who has a mental illness (44.7 million in 2016), 1 including depression and bipolar disorder.However, when the disorder involves distorted awareness and thinking, these illnesses are classified as psychiatric disorders. The prevalence of psychiatric disorders has increased over the years. 2 Schizophrenia is one of these psychiatric disorders and it is classified as a chronic and severe mental illness which affects about 23 million people worldwide. 3 The age of onset in women occurs during childbearing age between 25 and 35 years old, with a second peak occurring after menopause. 4The age range at the time of the first peak of the disease coincides with the child-bearing potential in women. Pregnancy can induce physiological changes, including the increase in the size of the fetal-placenta compartment, increase in renal filtration, body fluid volume and hepatic portal blood flow, changes in the expression and activity of drug metabolizing enzymes and drug transporters. 5,6 These changes affect absorption, distribution, metabolism and elimination of drugs, potentially resulting in a modification of the PK behaviour of drugs, including antipsychotics. [7][8][9] Pregnancy is known to affect hepatic drug metabolism but the underlying mechanisms are still unknown. Clearances of drugs metabolized by CYP2D6 and 3A4 increased, whereas those drugs metabolized by CYP1A2 decreased during pregnancy as compared to non-pregnant women. 10 For example, plasma levels of midazolam and metoprolol decrease in pregnant women due to the effect of changes in hepatic CYP3A4 and 2D6, respectively. 10,11 The clinical and ethical discussions on drug prescription during pregnancy focus on the safety of the fetus. The maintenance of drug efficacy in pregnant mothers amid al...

Pharmacokinetics, Pharmacodynamics and Dermal Distribution of 5-Methoxypsoralen Based on a Physiologically Based Pharmacokinetic Model to Support Phytotherapy Using Brosimum gaudichaudii

“…PK parameter observed mean PK parameter predicted mean (4) The model was considered acceptable if all predicted PK parameters were within twofold of the corresponding observed value (MFE 0.5 to 2.0), as is commonly applied in assessing PBPK model performance [29,30].…”

Physiologically based pharmacokinetic‐pharmacodynamic evaluation of meropenem plus fosfomycin in paediatrics

“…Given that the exposure parameters predicted by the full PBPK model were based on the physicochemical properties and demographical properties of the population, none of the exposure parameters from the literature were used in the model development, except for the comparison of summary statistics. The overall accuracy of the predicted pharmacokinetic parameters was assessed using the mean fold‐error (difference between predicted and observed in vivo values) 38,39 : The model was accepted when all predicted pharmacokinetic (PK) parameters were within two‐fold of the corresponding observed values (eg, MFE 0.5‐2.0) 38–41 …”

Antidepressants and Antipsychotics in Human Pregnancy: Transfer Across the Placenta and Opportunities for Modeling Studies

“…106 George et al developed a PBPK model-informed web-based interactive tool that allows the gestational-agedependent prediction of sertraline pharmacokinetics at various doses, predicting an increase in sertraline plasma clearance of up to 143% in the late third trimester across various therapeutic doses (50-200 mg). 101 Biesdorf et al and Zheng et al found that ziprasidone and olanzapine exhibit relatively stable plasma exposures during pregnancy, 103,106 whereas quetiapine and aripiprazole doses should be increased, especially in late pregnancy, according to the modeling results presented by Badhan et al and Zheng et al 104,105 Many antipsychotics and antidepressants are extensively metabolized; therefore, alterations in fraction unbound and hepatic intrinsic clearance are likely to significantly affect the maternal drug exposure. Al-though these studies accomplished their predefined goals, none of them has addressed the maternal-fetal transfer of these drugs.…”