Charles W. Flexner, MD
Johns Hopkins University School of Medicine, Baltimore, Maryland
Dr. Flexner opened the symposium by describing a case that raised several issues the meeting aimed to address. A 34-year-old African-American woman on methadone maintenance therapy began a regimen of nelfinavir plus Combivir (AZT/3TC) for HIV infection. Before long she reported opioid withdrawal symptoms to her clinician. She also revealed that she began taking Chinese herbs when starting antiretroviral therapy because a friend told her they would make the antiretrovirals more tolerable. Did her withdrawal symptoms represent?
- An interaction between the antiretrovirals and methadone
- A drug interaction mediated by the Chinese herbs
- An attempt to get a higher dose of methadone
Answering that question remains difficult because people with HIV infection typically take many medications. Documenting all the interactions would be a formidable task, according to Dr. Flexner. Among 45 recent discharges from The Johns Hopkins Hospital, Dr. Flexner noted, the number of pharmacologically active medications averaged 7 per patient. Among those discharged while taking a protease inhibitor (PI), the number of medications averaged 8.6 per patient.
Three overarching questions
Dr. Flexner posed three overarching questions about drug-drug interactions in people taking antiretrovirals and other medications. He outlined some possible answers:
- How to study the problem
- In-vitro models
- In-vivo models
- Observational versus prospective studies
- Database and population pharmacokinetics
He suggested that observational studies have become more attractive because mounting prospective studies of all potential interactions would be virtually impossible.
- How to manage the problem
- Putting more information in each drug's package insert
- Disseminating information via the Web
- Proposing general guidelines versus striving for individualized patient management
- Practicing therapeutic drug monitoring
Dr. Flexner doubted that more information in package inserts would help because the existing information is often overlooked. He endorsed a move toward individualized management versus general treatment guidelines.
- How to address special topics related to substance abuse
- Interactions between prescription medications and illicit drugs
- Interactions between complementary and alternative medications and prescription drugs
- Contaminants of illicit drugs
- Metabolites and enantiomers
- Role of plasma protein binding
- Role of drug transport proteins
Research has produced little information on interactions between prescription and illicit drugs, Dr. Flexner noted. Although the role of drug transporters may have an important impact on antiretroviral treatment outcome, these issues remain complicated and difficult to study.
Effect of staggered versus simultaneous PI dosing
Not all drug interactions are harmful, Dr. Flexner reminded attendees. Some can be beneficial; many are complex. One element of that complexity is whether the timing of drug administration affects two-way drug interactions. AIDS Clinical Trials Group (ACTG) investigators addressed that question in a study of staggered versus simultaneous administration of nelfinavir, saquinavir, and ritonavir. ACTG Protocol 378 enrolled 18 healthy volunteers and had a complex design involving six treatment periods for each person. The ACTG team reported several findings:
- When saquinavir was given 4 hours before ritonavir, saquinavir's area under the concentration-time curve (AUC) was reduced by 63% compared with saquinavir's AUC when the PIs were given simultaneously.
- When saquinavir was given 4 hours before nelfinavir, saquinavir's AUC was reduced by 68% compared with saquinavir's AUC when the PIs were given simultaneously.
- When nelfinavir was given 4 hours before saquinavir, saquinavir's AUC was increased by 76% compared with when the PIs were given simultaneously.
- Staggered dosing did not affect the AUCs of ritonavir or nelfinavir.
When given 48 hours before a second PI, Dr. Flexner added, ritonavir boosted concentrations of the later PI even though ritonavir had disappeared from the circulation.
Trying to correct interactions by dose adjustment
Another ACTG study, Protocol 365, determined whether interactions between rifabutin and the PI indinavir could be corrected by adjusting doses of those drugs. Rifabutin at a dose of 300 mg once daily decreases the AUC of indinavir by 32% when the PI is given at its standard dose of 800 mg every 8 hours. Co-administration at those doses triples rifabutin's AUC. ACTG 365 tested 1000 mg of indinavir every 8 hours given with 150 mg of rifabutin once daily in 10 people with HIV infection and in 18 healthy volunteers. The study yielded the following findings.
- The 1000-mg dose of indinavir coadministered with the 150-mg dose of rifabutin produced an indinavir AUC similar to that of standard-dose indinavir without rifabutin.
- The 150-mg dose of rifabutin coadministered with the higher dose of indinavir produced a rifabutin AUC 60% higher and a DA-rifabutin (major metabolite) AUC 125% higher than the AUCs of standard-dose rifabutin without indinavir.
- The clinical significance of the higher rifabutin and DA-rifabutin concentrations is unknown.
The take-home message from this study, Dr. Flexner proposed, is that dose adjustment can compensate for only some unwanted drug-drug interactions. Many interactions are unavoidable. For example, it may not be possible to adjust an antiretroviral dose that causes a lower methadone concentration. But drug interactions can be better understood, he concluded, and many can be managed better.