Can You Take Modafinil and Tadalafil Together?

Modafinil and tadalafil have not been directly tested together in a clinical drug-interaction study. However, human pharmacokinetic research suggests that regular modafinil use could reduce tadalafil exposure because modafinil can increase CYP3A4 activity, an enzyme pathway involved in tadalafil metabolism.

How large that effect might be with modafinil specifically is not known.

Do Modafinil and Tadalafil Interact?

Repeated modafinil treatment has been shown to increase CYP3A4 activity in humans, while tadalafil is predominantly cleared through hepatic CYP3A metabolism.

Greater CYP3A activity could therefore increase tadalafil metabolism and reduce the amount of tadalafil circulating in the body.

The available evidence makes a pharmacokinetic interaction plausible, but it does not establish how much tadalafil exposure changes when the two drugs are taken together.

Could Modafinil Reduce Tadalafil Exposure?

Wrishko et al. (2008) found that coadministering tadalafil with bosentan, a CYP3A4 inducer, reduced tadalafil AUC by 41.5% and peak concentration by approximately 27% in healthy men.

Bosentan was the inducer in this study, not modafinil. The 41.5% reduction therefore cannot be applied to people taking modafinil.

What the study does show is that CYP3A4 induction can substantially reduce tadalafil exposure. It does not tell us how large any reduction caused by modafinil would be.

Does Repeated Modafinil Use Matter More Than a Single Dose?

Rowland et al. (2018) measured CYP3A4 activity using midazolam after a single 200 mg dose of modafinil and after seven days of 200 mg daily.

After the single dose, midazolam AUC was approximately 0.98 of baseline, indicating little change in CYP3A4-mediated clearance.

After seven days of daily modafinil, the AUC ratio fell to approximately 0.66, corresponding to about 34% lower midazolam exposure and consistent with CYP3A4 induction.

This does not show that every intermittent pattern of modafinil use is free of interaction. It does show that the evidence for CYP3A4 induction is much stronger after repeated daily dosing than after a single 200 mg dose.

Can Taking Modafinil and Tadalafil Several Hours Apart Avoid the Interaction?

Taking modafinil and tadalafil several hours apart would not be expected to prevent an interaction caused by CYP3A4 induction.

The potential interaction is not simply a matter of both drugs being in the bloodstream at the same time. Repeated modafinil use can alter the activity of an enzyme involved in tadalafil metabolism.

Tadalafil also remains in the body for a relatively long period. Forgue et al. (2006) reported a mean terminal half-life of approximately 17.5 hours. With once-daily dosing, tadalafil reached steady state by about Day 5 and accumulated to approximately 1.6 times the exposure seen after a single dose.

No study has established a specific spacing interval that eliminates the potential interaction caused by CYP3A4 induction.

Does Tadalafil Affect Modafinil in Return?

In Ring et al. (2005), repeated tadalafil administration produced no clinically significant changes in the pharmacokinetics of midazolam or lovastatin, both CYP3A substrates.

Modafinil itself was not tested, so this should not be interpreted as direct evidence that tadalafil has no effect on modafinil concentrations.

The findings do suggest that tadalafil is unlikely to cause a substantial interaction by inhibiting or inducing CYP3A4.

References

Forgue, S. T., Patterson, B. E., Bedding, A. W., Payne, C. D., Phillips, D. L., Wrishko, R. E., & Mitchell, M. I. (2006). Tadalafil pharmacokinetics in healthy subjects. British Journal of Clinical Pharmacology, 61(3), 280–288. https://doi.org/10.1111/j.1365-2125.2005.02553.x

Ring, B. J., Patterson, B. E., Mitchell, M. I., Vandenbranden, M., Gillespie, J., Bedding, A. W., Jewell, H., Payne, C. D., Forgue, S. T., Eckstein, J., Wrighton, S. A., & Phillips, D. L. (2005). Effect of tadalafil on cytochrome P450 3A4-mediated clearance: Studies in vitro and in vivo. Clinical Pharmacology & Therapeutics, 77(1), 63–75. https://doi.org/10.1016/j.clpt.2004.09.006

Rowland, A., van Dyk, M., Warncken, D., Mangoni, A. A., Sorich, M. J., & Rowland, A. (2018). Evaluation of modafinil as a perpetrator of metabolic drug-drug interactions using a model informed cocktail reaction phenotyping trial protocol. British Journal of Clinical Pharmacology, 84(3), 501–509. https://doi.org/10.1111/bcp.13478

Wrishko, R. E., Dingemanse, J., Yu, A., Darstein, C., Phillips, D. L., & Mitchell, M. I. (2008). Pharmacokinetic interaction between tadalafil and bosentan in healthy male subjects. Journal of Clinical Pharmacology, 48(5), 610–618. https://doi.org/10.1177/0091270008315315