Physiologically Based Pharmacokinetic Modelling of UGT Substrate Drugs Lamotrigine and Raltegravir during Pregnancy

被引:3
作者
Berezowska, Monika [1 ]
Coppola, Paola [1 ]
Reddy, Venkatesh Pilla [1 ]
Sharma, Pradeep [1 ]
机构
[1] AstraZeneca, Clin Pharmacol & Quantitat Pharmacol, Biopharmaceut R&D, Cambridge CB1 9JS, England
来源
FUTURE PHARMACOLOGY | 2024年 / 4卷 / 02期
关键词
PBPK modelling; pregnancy; lamotrigine; raltegravir; ANTIEPILEPTIC DRUGS; HEALTHY; CLEARANCE; HEMODYNAMICS; TOLERABILITY; PLASMA; PHARMACODYNAMICS; GLUCURONIDATION; ELIMINATION; MONOTHERAPY;
D O I
10.3390/futurepharmacol4020018
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Pregnancy is associated with various physiological changes that can significantly impact the disposition of drugs. To further the insight into how pregnancy affects the pharmacokinetics of drugs at different stages, clinical studies can be simulated using Physiologically Based Pharmacokinetic modelling. PBPK modelling of drugs metabolised by Phase I enzymes (CYPs) in pregnant population models had been reported in the past, while its use in Phase II (UGTs) is not known. In this study, based on the results of a recent meta-analysis, lamotrigine (UGT1A4) and raltegravir (UGT1A1) were selected as candidate drugs, and pregnancy-specific models were developed for both using the Simcyp v.21 simulator. A middle-out strategy was used where previously published drug parameters were adapted from a minimal to a full PBPK model to allow their application for the pregnancy population models using Simcyp PBPK software. Adapted models were successfully validated against observed clinical data both qualitatively (visual overlay of plasma concentrations on graphs) and quantitatively (calculating the predicted/observed ratios for AUC, Cmax and CL as well as statistical analysis using model prediction power metrics). They were then applied to predict the PKs of both drugs in pregnancy population models. The temporal changes in maternal enzymatic activities during gestation were modelled based on in vitro data reported in literature and default relationships encoded in the Simcyp platform for UGT1A1 and UGT1A4, respectively. Our study demonstrates the successful development and validation of a PBPK model for LTG and RTG in pregnancy population models. Future work with additional UGT1A4 substrate drugs using the proposed changes in UGT1A4 activity may enable validating the pregnancy population model and its subsequent use for the prospective prediction of PK.
引用
收藏
页码:317 / 335
页数:19
相关论文
共 67 条
  • [1] Anatomical, Physiological and Metabolic Changes with Gestational Age during Normal PregnancyA Database for Parameters Required in Physiologically Based Pharmacokinetic Modelling
    Khaled Abduljalil
    Penny Furness
    Trevor N. Johnson
    Amin Rostami-Hodjegan
    Hora Soltani
    [J]. Clinical Pharmacokinetics, 2012, 51 (6) : 365 - 396
  • [2] Plasma volume expansion across healthy pregnancy: a systematic review and meta-analysis of longitudinal studies
    Aguree, Sixtus
    Gernand, Alison D.
    [J]. BMC PREGNANCY AND CHILDBIRTH, 2019, 19 (01)
  • [3] Pharmacokinetic interaction study between eslicarbazepine acetate and lamotrigine in healthy subjects
    Almeida, L.
    Nunes, T.
    Sicard, E.
    Rocha, J. -F.
    Falcao, A.
    Brunet, J. -S.
    Lefebvre, M.
    Soares-da-Silva, P.
    [J]. ACTA NEUROLOGICA SCANDINAVICA, 2010, 121 (04): : 257 - 264
  • [4] Assessment of the pharmacokinetics of co-administered maraviroc and raltegravir
    Andrews, Emma
    Glue, Paul
    Fang, Juanzhi
    Crownover, Penelope
    Tressler, Randall
    Damle, Bharat
    [J]. BRITISH JOURNAL OF CLINICAL PHARMACOLOGY, 2010, 69 (01) : 51 - 57
  • [5] Physiologically Based Pharmacokinetic modelling of drugs in pregnancy: A mini-review on availability and limitations
    Berezowska, Monika
    Sharma, Pradeep
    Reddy, Venkatesh Pilla
    Coppola, Paola
    [J]. FUNDAMENTAL & CLINICAL PHARMACOLOGY, 2024, 38 (03) : 402 - 409
  • [6] Pregnancy Increases the Renal Secretion of N1-methylnicotinamide, an Endogenous Probe for Renal Cation Transporters, in Patients Prescribed Metformin
    Bergagnini-Kolev, Mackenzie C.
    Hebert, Mary F.
    Easterling, Thomas R.
    Lin, Yvonne S.
    [J]. DRUG METABOLISM AND DISPOSITION, 2017, 45 (03) : 325 - 329
  • [7] Relative bioavailability of lamotrigine chewable dispersible tablets administered rectally
    Birnbaum, AK
    Kriel, RL
    Im, Y
    Remmel, RP
    [J]. PHARMACOTHERAPY, 2001, 21 (02): : 158 - 162
  • [8] Effect of Ginkgo Biloba on the Pharmacokinetics of Raltegravir in Healthy Volunteers
    Blonk, Maren
    Colbers, Angela
    Poirters, Anne
    Schouwenberg, Bas
    Burger, David
    [J]. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2012, 56 (10) : 5070 - 5075
  • [9] Raltegravir in HIV-1-Infected Pregnant Women: Pharmacokinetics, Safety, and Efficacy
    Blonk, Maren I.
    Colbers, Angela P. H.
    Hidalgo-Tenorio, Carmen
    Kabeya, Kabamba
    Weizsaecker, Katharina
    Haberl, Annette E.
    Molto, Jose
    Hawkins, David A.
    van der Ende, Marchina E.
    Gingelmaier, Andrea
    Taylor, Graham P.
    Ivanovic, Jelena
    Giaquinto, Carlo
    Burger, David M.
    [J]. CLINICAL INFECTIOUS DISEASES, 2015, 61 (05) : 809 - 816
  • [10] A systematic review of pregnancy-related clinical intervention of drug regimens due to pharmacokinetic reasons
    Borda, Lauren A.
    Nagard, Mats
    Boulton, David W.
    Venkataramanan, Raman
    Coppola, Paola
    [J]. FRONTIERS IN MEDICINE, 2023, 10