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Clinical Trial
, 84 (3), 501-509

Evaluation of Modafinil as a Perpetrator of Metabolic Drug-Drug Interactions Using a Model Informed Cocktail Reaction Phenotyping Trial Protocol

Affiliations
Clinical Trial

Evaluation of Modafinil as a Perpetrator of Metabolic Drug-Drug Interactions Using a Model Informed Cocktail Reaction Phenotyping Trial Protocol

Angela Rowland et al. Br J Clin Pharmacol.

Abstract

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.

Keywords: cytochrome P450; drug interaction.

Figures

Figure 1
Figure 1
Spaghetti plot showing change in AUC from baseline (Day 0), following a single dose (Day 2) and dosing of modafinil to steady state (Day 8). Panel A: caffeine; Panel B: dextromethorphan; Panel C: losartan; Panel D: midazolam; Panel E: omeprazole. Dashed lines represent individual participant data, while the solid line represents the cohort mean
Figure 2
Figure 2
Spaghetti plot showing change in C max from baseline (Day 0), following a single dose (Day 2) and dosing of modafinil to steady state (Day 8). Panel A: caffeine; Panel B: dextromethorphan; Panel C: losartan; Panel D: midazolam; Panel E: omeprazole. Dashed lines represent individual participant data, while the solid line represents the cohort mean
Figure 3
Figure 3
Representative midazolam concentration–time curves (P01) in the absence of modafinil (dotted line with squares), following a single modafinil dose (broken line with triangles) and following steady state dosing of modafinil (solid line with circles)
Figure 4
Figure 4
Representative omeprazole concentration–time curves (P01) in the absence of modafinil (dotted line with squares), following a single modafinil dose (broken line with triangles) and following steady state dosing of modafinil (solid line with circles)

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