TY - JOUR
T1 - Evaluation of modafinil as a perpetrator of metabolic drug-drug interactions using a model informed cocktail reaction phenotyping trial protocol
AU - Rowland, Angela
AU - Van Dyk, Madele
AU - Warncken, David
AU - Mangoni, Arduino
AU - Sorich, Michael
AU - Rowland, Andrew
PY - 2018/3
Y1 - 2018/3
N2 - Aim: To evaluate the capacity for modafinil to be a perpetrator of metabolic drug–drug interactions by altering cytochrome P450 activity following a single dose and dosing to steady state. Methods: A single centre, open label, single sequence cocktail drug interaction trial. On days 0, 2 and 8 participants were administered an oral drug cocktail comprising 100 mg caffeine, 30 mg dextromethorphan, 25 mg losartan, 1 mg midazolam and 20 mg enteric-coated omeprazole. Timed blood samples were collected prior to and for up to 6 h post cocktail dosing. Between days 2 and 8 participants orally self-administered 200 mg modafinil each morning. Results: Following a single 200 mg dose of modafinil mean (± 95% CI) AUC ratios for caffeine, dextromethorphan, losartan, midazolam and omeprazole were 0.95 (± 0.08), 1.01 (± 0.35), 0.97 (± 0.10), 0.98 (± 0.10) and 1.36 (± 0.06), respectively. Following dosing of modafinil to steady state (200 mg for 7 days), AUC ratios for caffeine, dextromethorphan, losartan, midazolam and omeprazole were 0.90 (± 0.16), 0.79 (± 0.09), 0.98 (± 0.11), 0.66 (± 0.12) and 1.90 (± 0.53), respectively. Conclusions: These data support consideration of the risk of clinically relevant metabolic drug–drug interactions perpetrated by modafinil when this drug is co-administered with drugs that are primarily cleared by CYP2C19 (single modafinil dose or steady state modafinil dosing) or CYP3A4 (steady state modafinil dosing only) catalysed metabolic pathways.
AB - Aim: To evaluate the capacity for modafinil to be a perpetrator of metabolic drug–drug interactions by altering cytochrome P450 activity following a single dose and dosing to steady state. Methods: A single centre, open label, single sequence cocktail drug interaction trial. On days 0, 2 and 8 participants were administered an oral drug cocktail comprising 100 mg caffeine, 30 mg dextromethorphan, 25 mg losartan, 1 mg midazolam and 20 mg enteric-coated omeprazole. Timed blood samples were collected prior to and for up to 6 h post cocktail dosing. Between days 2 and 8 participants orally self-administered 200 mg modafinil each morning. Results: Following a single 200 mg dose of modafinil mean (± 95% CI) AUC ratios for caffeine, dextromethorphan, losartan, midazolam and omeprazole were 0.95 (± 0.08), 1.01 (± 0.35), 0.97 (± 0.10), 0.98 (± 0.10) and 1.36 (± 0.06), respectively. Following dosing of modafinil to steady state (200 mg for 7 days), AUC ratios for caffeine, dextromethorphan, losartan, midazolam and omeprazole were 0.90 (± 0.16), 0.79 (± 0.09), 0.98 (± 0.11), 0.66 (± 0.12) and 1.90 (± 0.53), respectively. Conclusions: These data support consideration of the risk of clinically relevant metabolic drug–drug interactions perpetrated by modafinil when this drug is co-administered with drugs that are primarily cleared by CYP2C19 (single modafinil dose or steady state modafinil dosing) or CYP3A4 (steady state modafinil dosing only) catalysed metabolic pathways.
KW - cytochrome P450
KW - drug interaction
UR - http://www.scopus.com/inward/record.url?scp=85040188386&partnerID=8YFLogxK
U2 - 10.1111/bcp.13478
DO - 10.1111/bcp.13478
M3 - Article
SN - 0306-5251
VL - 84
SP - 501
EP - 509
JO - British Journal of Clinical Pharmacology
JF - British Journal of Clinical Pharmacology
IS - 3
ER -