An extended release formulation breaks through
by Chael Needle
Based on results from the VERxVE study, the FDA recently approved Viramune XR for use in antiretroviral combination therapy to treat HIV-1 infection in adults. “XR” stands for “extended release,” offering patients a one 400mg pill, once-daily dosing option. Until now, Boehringer Ingelheim, makers of Viramune (nevirapine), had offered an immediate-release (IR), 200mg form of the drug with a twice-daily dosing.
“Development of the extended-release formulation began in 2004 to provide a once-a-day preparation that was as effective as twice-a-day and a different delivery system,” Dr. Joseph C. Gathe, Jr., lead investigator of the VERxVE clinical trial and clinical instructor in the Department of Internal Medicine at Baylor College of Medicine, Houston, tells A&U.
The pharmacokinetics—how drugs move through the body—have been shown to support once-daily dosing with XR. Evaluating the safety and efficacy of XR in comparison with IR, both in combination with TDF/FTC, VERxVE, a randomized, double-blind, double-dummy, parallel group, active controlled, multinational trial, enrolled treatment-naive women with CD4+ cell counts less than 250 cells/mm3 and men with CD4+ cell counts less than 400 cells/mm3. Out of a total of 1,068 participants, 1,013 adult patients were randomized and 1,011 received either Viramune XR or IR, each in combination with Truvada.
Eighty percent of those on XR versus seventy-five percent on IR achieved the study endpoint of a viral load of less than 50 copies/mL at the end of forty-eight weeks of treatment.
Alongside achieving a sustained virological response from the new formulation, the researchers were also interested in evaluating safety. “Whenever you have any compound, you want the drug to get into the system [at a] high enough [level] to take care of the problem but low enough to not cause any toxicities. Viramune has been a part of HIV treatment for fifteen years, and the company and the drug designers asked, ‘Can we try to make this a more convenient product, not only making it a once-a-day medication that would be in line with some of the other antiretroviral options while not exposing the patients to quite as much drug if possible?’”
VERxVE demonstrated that the safety profile of Viramune XR is comparable to Viramune IR, as well. After the fourteen-day lead-in period of 200mg, once-daily dosing, the incidence of any hepatic event was six percent for those on XR compared to nine percent for those on IR. The rate of symptomatic hepatic events was comparable: XR at two percent versus IR at three percent. In each of the study arms, three percent of patients experienced grade 2 or higher rash, which can be severe or life-threatening. Other potential side effects associated with Viramune are facial edema, toxic epidermal necrolysis and hypersensitivity reactions, among others.
“Nevirapine is one of the agents that we’ve had the most experience with, and we learned early on, in the beginning of the last decade, about the potential toxicities of Viramune, mainly skin rash and problems with the liver in patients, that were not clear when the drug was first being studied,” says Dr. Gathe. “Now that we better understand these potential side effects, clinicians and patients can be apprised of them, which can potentially decrease the risk of developing one of them by giving the drug only to patients that have less of a chance of having one of these toxicities. So the CD4+ cell count guidelines for men and women regarding initiation of Viramune are in place to decrease the likelihood of developing hepatotoxicity.”
Moving forward, the primary research question that needs to be answered is the extent of Viramune XR’s durability, says Dr. Gathe. “If you treat patients longer, do you still see the same effect? Are there any toxicities that weren’t seen in the first forty-eight weeks? So the research question that has been asked and at present time being analyzed is, What’s going on with patients down the line?” Results from 144-week VERxVE data will help begin to answer these questions.
For those patients interested in switching from IR to XR (a practice supported by the TRANxITION study) or starting XR for the first time, educational materials are available on the Web and at physicans’ offices. Boehringer Ingelheim is also offering a co-pay savings card to help defray the cost of Viramune XR and has expanded its Virology Patient Assistance Program to help with long-term treatment access needs. Says Dr. Gathe: “Now, the job is clinician and patient education.”
Chael Needle wrote about Dr. C. Everett Koop’s recent account of the early days of AIDS in the April issue.