12.18.23 OMA Board Book

con�nue to be underrepresented in research and in clinical trials, making it difficult to obtain the necessary data to inform dosing of a newly marketed drug in individuals with obesity.” “ People with obesity deserve to know if the drugs they use are safe and effec�ve for them —and so do their doctors,” says Joe Nadglowski, President and CEO of OAC, an 80,000-member advocacy organiza�on for people with obesity. “These drugs are used every day by people who don’ t know they might not be effec�ve, and include treatments for depression, schizophre nia, emergency contracep�on, preven�ng organ transplant rejec�on, infec�ons, and cancer. ” Not all drugs behave differently in the bodies of people with obesity, but some clearly do. In people with obesity, lipophilic drugs can be absorbed by fat, reducing the level of drug circula�ng in the blood . A lower level of drug in the bloodstream means the drug may require a longer �me to become effec�ve , or it may n ever reach effec�ve levels . This effect can lead to the mistaken conclusion that the drug is ineffec�ve, which can pose serious risks. For example, the drug br expiprazole, marketed under the brand name Rexul�, is used to treat schizophrenia and depression. The studies conducted to demonstrate Rexul� ’s safety and efficacy prior to launch specifi cally excluded people with higher BMI’s, 4 despite reports showing 58 % of people with schizophrenia have obesity. 5 More recent studies, whose co-authors include two former FDA review division heads, revealed that brexpiprazole takes significantly longer to reach effec�ve levels in people with obesity, and those who are also CYP2D6 poor metabolizers never reach effec�ve levels . 6 These experts proposed dosing changes for such pa�ents that have never been acted on. Underdosing may lead pa�ents and their doctors to conclude the drug is ineffec�ve and discon�nue the medica�on , or unknowingly con�nue its use at an ineffec�ve level . A person with untreated or undertreated schizophrenia can be at risk of harming themselves or o thers or commi�ng suicide. A second consequence of obesity can be a significant increase in drug half-life. An increased half-life may lead to inadvertent drug-drug interac�ons. For example, posaconazole, an an�fungal marketed under the brand name No xafil, was not fully tested in people with obesity prior to approval. The half-life of posaconazole is significantly longer in pa�ents with obesity than in pa�ents at a normal BMI. 7 Because posaconazole is a strong inhibitor of CYP3A4, a liver enzyme that metabolizes a high percentage of all drugs, people with obesity are at risk of prolonged drug- drug interac�ons for weeks a�er stopping posaconazole . For instance, numerous cancer drugs already carry warnings to wait 3- 5 drug half- lives a�er stopping a drug 4 Applica�on Number: 205422Orig1s000 and 205422Orig2s000 Clinical Pharmacology and Biopharmaceu�cs Review(s). US Food and Drug Administra�on Center for Drug Evalua�on and Research (FDA CDER). htps://www.accessdata.fda.gov/drugsa�da_docs/nda/2015/205422Orig1Orig2s000ClinPharmR.pdf 5 Annamalai A, Kosir U, Tek C. Prevalence of obesity and diabetes in pa�ents with schizophrenia. World J Diabetes 2017;8:390. htps://doi.org/10.4239/wjd.v8.i8.390. 6 htps://accp1.onlinelibrary.wiley.com/doi/abs/10.1002/jcph.1946 7 Greenblat DJ, Harmatz JS, Ryan MJ, Chow CR. Sustained Impairment of Lurasidone Clearance A�er Discon�nua�on of Posaconazole: Impact of Obesity, and Implica�ons for Pa�ent Safety. J Clin Psychopharmacol 2018;38:289 – 95. htps://doi.org/10.1097/JCP.0000000000000892.