Roland LopezUniversity of Washington2009 PharmD Candidate

August 29th , 2008

Personal interest• Friends with shift work sleep disorder (SWSD)

Irregular work patterns Healthcare and military

Novel mechanism of action• Atypical stimulants

Typical stimulant Caffiene (Adenosine) Cocaine and amphetimines (Dopamine and NE)

Recent interesting articles Athletic enhancing drugs?

Sprinter Kelli White, 2004

Academic enhancing drugs? Nature article readers , 2008

First developed in France as Modiodal and 1st available in 1994

Available to the US in 1998 as Provigil Provigil is a racemate

Tried to market towards ADHD children as Sparlon in 2006 but was rejected by FDA due to concern of increased risk of Stevens-Johnsons Syndrome (1 case reported)

Nuvigil (armodafinil), the R-enantiomer, availble in 2007 The R-enantiomer is has a longer half-life and is not marketed towards

children

Provigil has been popular in many military applications Covert operations Helicopter pilots Fighter pilots

Narcolepsy, obstructive sleep apnea/hypopnea syndrome (OSAHS): Oral: Initial: 200 mg as a single daily dose in the morning.

Shift work sleep disorder (SWSD): Initial: 200 mg as a single dose taken ~1 hour prior to start of work shift.

ADHD (unlabeled use): Oral: 100-300 mg once daily.

The exact mechanism of action is unclear.

It does not appear to alter the release of dopamine or norepinephrine and this thought to decrease GABA-mediated neurotransmission. • GABA is an inhibitory neurotransmitter

Prmary metabolic route• Amide hydrolysis

Exact amidase or mechanism has not been identified but is thought to exist hepatically

Minor metabolic routes• Cytochrome P450

P-450 1A2, 2B6, 3A4/5, 2C9, 2C19, and PGP

Inducer of CYP3A4

Reversible inhibitor of 2C19

GeneMedRx is a software tool designed tohelp physicians predict whether or not drugs are safe and effective for patients.

This program was able to list 10 known interactions of Provigil and Nuvigil.

http://www.genemedrx.com/public/home.html

Cyclosporine and Modafinil• A case is reported of a 50% reduction in

cyclosporine. Because of narrow therapeutic range of cyclsporine, this combination should be avoided.

Modafinil and Ethinyl Estradiol (low dose)• A clinical study shows decreased max plasma

concentration of ethinyl estradiol. This drug interaction may be especially significant with low dose OCs since there is less ethinyl estradiol in the mini-pill. Consideration for increased dosage of oral contraceptive to 50 ug or barrier contraception.

Modafinil and Clomipramine• A case is reported of elevated clomipramine concentrations

which may be explained by CYP2C19 modafinil inhibition. This patient was a CYP2D6 poor metabolizer.

Clozapine and Modafinil• A case report of an 84% increase in clozapine serum

concentration in approximately 40 days for this combination. Signs of toxiciy were seen as a gait disturbance and hypoxemia. The basis for this interaction could be due to inhibition of 2C19 activity by modafinil. Monitoring serum concentrations and toxicity signs are recommended for this combination.

• Note that the basis of these interactions could be explained by CYP2D6 poor metabolizer status and shunting metabolism to the accessory 2C19 pathway.

Although GeneMedRx was able to list and identify 10 known interactions, there were 14 new interactions identified through PubMed, British National Formulary, and product insert searches.

These new notes were then included in the most recent update of GeneMedRx.

Clozapine and Modafinil• Cyp2C19 inihibition(Case report with modafinil)

Modafinil/armodafinil and Propranolol• Cyp2C19 inhibition

Modafinil/armodafinil and Phenytoin• 2C19 inhibition

Modafinil/armodafinil and Diazepam• 2C19 inhibition

Modafinil/armodafinl and Midazolam• 3A4 induction, decreased AUC of midazolam 34%

Armodafinil/modafinil and Omeprazole• Clinical study shows that armodafinil coadministration increased the

AUC of oral omeprazole by approximately 38% compared with administration of omeprazole alone.

Modafinil/armodafinil and PGP• Not listed in LexiComps, and only one isomer is a substrate,

armodafinil and l-modafinil.

Modafinil/armodafinil and Ketoconazole• Possible inhibition of modafinil/armodafinil since ketoconazole is a

powerful 3A4 inhibitor But no studies have shown this, only a warning from the package insert.

Most probable pharmacy scenarios: Modafinil /armodafinil and OCP Modafinil/armodafinil and pheytoin Modafinil/armodafinil and cyclosporine Modafinil/armodafinil and diazepam

• Proper patient education/counseling is key

Bjornsson TD, Callaghan JT, Einolf HJ, et al, “The Conduct of In Vitro and In Vivo Drug-Drug Interaction Studies: A PhRMA Perspective,” J Clin Pharmacol, 2003, 43(5):443-69.

Darwish M, Kirby M, Robertson P Jr, Hellriegel ET. "Interaction profile of armodafinil with medications metabolized by cytochrome P450 enzymes 1A2, 3A4 and 2C19 in healthy subjects." Clin Pharmacokinet. (2008): 61-74.

FDA. Provigil. 17 August 2007. 25 August 2008 <http://www.fda.gov/cder/foi/label/2007/020717s020s013s018lbl.pdf>.

FDA. Nuvigil. 15 June 2007. 26 August 2008 <http://www.fda.gov/cder/foi/label/2007/021875lbl.pdf>. James King, PhD. Cephalon Sicentist Roland Lopez. 24 August 2008. R, Bhat SK and Galang. "Modafinil-Associated Clozapine Toxicity." Am J Psychiatry (2002): 1243-1244. Report, The Carlat Psychiatry. Sparlon and ADHD: The Power of a 7-Year Old. September 2006. 26

August 2008 <http://www.thecarlatreport.com/index.asp?page=wp3162007141331>. Robertson P Jr, Hellriegel ET, Arora S, Nelson M. "Effect of modafinil at steady state on the single-

dose pharmacokinetic profile of warfarin in healthy volunteers." J Clin Pharmacol. (2002 ): 205-14. Robertson P Jr, Hellriegel ET, Arora S, Nelson M. "Effect of modafinil on the pharmacokinetics of

ethinyl estradiol and triazolam in healthy volunteers." Clin Pharmacol Ther. (2002 ): 46-56. Robertson P Jr, Hellriegel ET. "Clinical pharmacokinetic profile of modafinil." Clin Pharmacokinet.

(2003): 123-37. UpToDate. Modafinil: Drug information . December 2007. 28th August 2008

<http://www.uptodateonline.com.offcampus.lib.washington.edu/online/content/topic.do?topicKey=drug_l_z/53350&selectedTitle=1~38&source=search_result>.

USA Today. Sprinter reveals career demise. 2 December 2004. 26 August 2008. Wikipedia. Modafinil. 2008. 27 August 2008 <http://en.wikipedia.org/wiki/Modafinil>.

Wong YN, King SP, Simcoe D, Gorman S, Laughton W, McCormick GC, Grebow P. "Open-label, single-dose pharmacokinetic study of modafinil tablets: influence of age and gender in normal subjects." J Clin Pharmacol. (1999 ): 281-8.

Wong YN, Simcoe D, Hartman LN, Laughton WB, King SP, McCormick GC, Grebow PE. "A double-blind, placebo-controlled, ascending-dose evaluation of the pharmacokinetics and tolerability of modafinil tablets in healthy male volunteers." J Clin Pharmacol. (1999 ): 30-40.