PI-074 - A PHYSIOLOGICALLY BASED PHARMACOKINETIC (PBPK) MODEL EVALUATING THE DRUG-DRUG INTERACTION (DDI) POTENTIAL BETWEEN LAMOTRIGINE (LMT) AND ACETAMINOPHEN (APAP).

E. Scholz¹, O. Della Pasqua², J. Bloomer³, L. rebar⁴, H. Tracey³, K. Taskar⁵; ¹GlaxoSmithKline, Wake Forest, NC, USA, ²GlaxoSmithKline, London, England, United Kingdom, ³GlaxoSmithKline, Ware, United Kingdom, ⁴GlaxoSmithKline, Collegeville, PA, USA, ⁵GlaxoSmithKline, Stevenage, Hertfordshire, United Kingdom.

Background: Two small clinical studies1,2 reported a 20% decrease in LMT AUC following coadministration with APAP. As LMT is majorly metabolized by UGT1A4, it is thought that LMT metabolism is increased due to UGT1A4 induction by APAP. PBPK modeling was used to investigate the prevalence and severity of the DDI in larger, simulated trials in healthy volunteers and extended to elderly and pediatric populations.

Methods: Mechanistic LMT and APAP PBPK models were developed in Simcyp® v21.1 and qualified using clinical data. LMT mechanistic clearance was included and verified using clinical DDIs with known UGT inducers rifampicin and ritonavir. As there are limited data and tools to generate in vitro values for UGT induction, the APAP model was updated to include UGT1A4 induction using one of the available clinical DDI reports1, while the second clinical study was used for verification of the induction effect2. Lastly, the verified DDI model was scaled to larger sample sizes (n=4,000, n=10,000) and applied in special populations (n=4,000). DDI severity was evaluated using AUC ratios (AUCRs).

Results: In large trials of healthy volunteers, the DDI extent (geometric mean (GM) AUCR=0.84) was similar to published clinical studies (GM AUCRs=0.821 and 0.842), with a similar trend in the elderly (GM AUCR=0.82) and pediatric (GM AUCR=0.84) simulations. Across all populations, zero subjects experienced a strong induction effect (AUCR=0-0.19), and only 0.2%, 0.4%, and 0.03% of healthy, elderly, and pediatric subjects, respectively, experienced moderate induction (AUCR=0.2-0.49).

Conclusion: PBPK was effectively used to simulate the DDI using large sample sizes and special populations, which is not often practically possible. Based on our simulations, there is very low likelihood of clinically relevant LMT metabolism induction by APAP.

1. Gastrup, S., T. B. Stage, P. B. Fruekilde, and P. Damkier. 2016. 'Paracetamol decreases steady-state exposure to lamotrigine by induction of glucuronidation in healthy subjects', Br J Clin Pharmacol, 81: 735-41.
2. Depot, M., J. R. Powell, J. A. Messenheimer, G. Cloutier, and M. J. Dalton. 1990. 'Kinetic effects of multiple oral doses of acetaminophen on a single oral dose of lamotrigine', Clin Pharmacol Ther, 48: 346-55.