Physiologically Based Pharmacokinetic modelling of the Drug-Drug Interaction between Ivacaftor and Lefamulin in Cystic Fibrosis patients
Magali Amiel; Alice Ke; Steven P. Gelone; Hannah M. Jones; Wolfgang Wicha
Certara, Nabriva Therapeutics
Physiologically-based pharmacokinetic (PBPK) modeling of the combination of ivacaftor and lefamulin in Cystic Fibrosis patients
Wolfgang W. Wicha1, Magali Amiel2, Alice Ke2, Hannah Jones2, Steven P. Gelone3
1 Nabriva Therapeutics GmbH, Vienna, Austria; 2PBPK Consultancy Services, Certara UK Ltd, Simcyp Division, 1 Concourse Way, Level 2-Acero, Sheffield, S1 2BJ, United Kingdom; 3 Nabriva Therapeutics US, Inc., Fort Washington, PA, USA
INTRODUCTION
Lefamulin (Xenleta®) is pleuromutilin antibiotic approved for the treatment of community-acquired bacterial pneumonia in adults. It is currently being evaluated as a potential treatment for bacterial exacerbations in Cystic Fibrosis (CF) patients caused by S. aureus. When administered orally, lefamulin is a moderate CYP3A inhibitor and co-administration with some CF transmembrane conductance regulator (CFTR) modulators such as ivacaftor, may result in a pharmacokinetic (PK) interaction. To evaluate the potential for a drug-drug interaction (DDI), a PBPK modeling approach was utilized to characterize and assess the potential for a DDI between oral lefamulin and ivacaftor.
METHODS
- PBPK models were derived and simulated using Version 20 of the Simcyp™ Simulator utilizing the minimal PBPK model. Absorption was simulated using the Advanced Dissolution, Absorption, and Metabolism (ADAM) model.
- Lefamulin:
- o A PBPK model for lefamulin was previously developed from clinical and in vitro data and validated against observed single and multidose regimens.
- Ivacaftor:
- o A previously published PBPK model for ivacaftor4 was used as a basis for development of the minimal PBPK model
- o Once the ivacaftor model was developed, it was validated by simulating concentration-time profiles for repeat oral doses (5 to 14 days) of 50 mg QD and 150 mg BID, comparing exposures with published observed data7,8,9.
PBPK Model Verification For Drug-drug Interaction Studies
Ivacaftor
- To characterize the contribution of CYP3A4 to the overall clearance for ivacaftor, simulations were run for combinations with itraconazole, fluconazole and ketoconazole (Simcyp Version 20 Standard Compound Library) and the ivacaftor exposures were compared with observed clinical data7,8,9.
Lefamulin
- Simulations were made and compared with observed clinical drug-drug interaction studies with ketoconazole, rifampin, and midazolam. Of note, the final enzyme competitive inhibition constant (Ki) varied between IV and oral formulations of lefamulin.
Evaluation of Lefamulin and Ivacaftor Drug-drug Interaction Potential
- Cystic Fibrosis Population
- o Patient demographic model inputs were derived from the literature and included to the North European Caucasian population preidentified in Simcyp Simulator. (Keogh 2020, Lai 1999)
- o Validations studies were conducted to evaluate predictability of the PBPK model in the cystic fibrosis population8.
- Application simulations using various dosing regimen for both ivacaftor and Lefamulin in CF
RESULTS
PBPK Model Development and Validation
- In validation studies, simulations for the final ivacaftor PBPK model revealed mean AUC0-∞ and Cmax values within 1.28-fold that of the observed values in healthy volunteers.
- Simulations of cystic fibrosis patients given single doses of ivacaftor resulted in AUC0-∞ and Cmax values within 1.4-fold of the observed values.
PBPK Model Verification For Drug-drug Interaction Studies
Simulated geometric mean rations for AUC and Cmax were within 1.5-fold of the observed values for itraconazole, fluconazole, and ketoconazole, respectively.
Evaluation of Lefamulin and Ivacaftor Drug-drug Interaction Potential
- o Simulations combining oral ivacaftor with IV lefamulin resulted in non-significant impacts on ivacaftor pharmacokinetics with GMRs for AUC of ≤1.24 and Cmax of ≤1.22.
- o Simulated effects of oral lefamulin on the pharmacokinetics of ivacaftor were classified as mild to moderate inhibition with GMRs of ≤2.09 for AUC and ≤1.92 for Cmax, with greater inhibition observed when lefamulin was given as multiple doses vs. as a single dose.
DISCUSSION
- Simulations of PBPK models for lefamulin and ivacaftor were in reasonable agreement with observed clinical pharmacokinetic data with a ≤1.4-fold difference in AUC and Cmax values.
- For drug-drug interaction simulation studies of ivacaftor combined with IV lefamulin in cystic fibrosis patients, lefamulin’s effects on ivacaftor were non-significant.
- Simulated changes in ivacaftor AUC when administer with oral lefamulin in cystic fibrosis patients was classified as weak to moderate.
- Lefamulin simulations resulted in a lesser impact on ivacaftor AUC as compared to combinations with fluconazole (a know moderate CYP3A inhibitor).
Taken together, these results suggest a low liability for a CYP3A-mediated drug-drug interaction between lefamulin and ivacaftor in cystic fibrosis patients.
References:
- ) XENLETA® (lefamulin) [package insert]. Fort Washington, PA: Nabriva Therapeutics; 2021
- ) Study to Assess the Safety and PK of Oral and IV Xenleta in Adults With Cystic Fibrosis. https://clinicaltrials.gov/ct2/show/NCT05225805
- ) KALYDECO® (ivacaftor) [package insert]. Boston, MA: Vertex Pharmaceuticals; 2021
- ) Tsai A, et. al. (2020). Physiologically based pharmacokinetic modeling of CTFR modulation in people with cystic fibrosis transitioning from mono or dual regimens to triple-combination Elexacaftor/Tezacaftor/Ivacaftor. Pulm Ther 6: 275-286
- ) Keogh RH, et al. (2020). The changing demography of the Cystic Fibrosis population: forecasting future numbers of adults in the UK. Sci Rep 10:10660.
- ) Lai HC, et al. (1999). Comparison of growth status of patients with cystic fibrosis between the United States and Canada. Am J Clin Nutr 69: 531-8.
- ) Garg, et al (2019). Pharmacokinetic and Drug–Drug Interaction Profiles of the Combination of Tezacaftor/Ivacaftor. Clin Transl Sci 12: 267–275.
- ) FDA Center For Drug Evaluation and Research (2012). Ivacaftor Clinical Pharmacology and Biopharmaceutics Review(s). Application Number: 203188Orig1s000.
- ) FDA Center For Drug Evaluation and Research (2017). Tezacaftor/Ivacaftor Clinical Pharmacology and Biopharmaceutics Review(s). Application Number: 210491Orig1s000.
