By Harvey S. Bartnof, MD, Staff Physician at AVERI, AIDS Virus Education and Research Institute in San Francisco, California

PART 5 :
   I. Other Saquinavir Reports:
     --   Pregnant women have low saquinavir levels with standard dosing
     --   Twice daily saquinavir as either Fortovase or Invirase, with ritonavir
   II. NIH Proposes New Drug Interaction Program and Information Resource
   III. FDA Drafting New Document Targeting HIV Pharmacology

Pregnant Women Have Low Saquinavir Levels with Standard Dosing
Another interesting poster by Edward P. Acosta, PharmD of the University of Alabama at Birmingham and colleagues concluded that standard saquinavir (Fortovase) dosing is inadequate for pregnant women. The authors were from PACTG (Pediatric AIDS Clinical Trials Group) 386. Four pregnant women were taking saquinavir (Fortovase) 1,200 mg 3-times daily plus 2 NRTI drugs, AZT (Retrovir) and 3TC (Epivir). The 4 women included 3 Blacks and 1 Hispanic, with a median (average, half above, half below) age of 28 years, a median gestation (pregnancy length) of 31 weeks, a median weight of 94 kilograms (207 pounds), a median baseline CD4 count of 208 cells per microliter and a median baseline HIV RNA of 2.6 log (400) copies per milliliter. Using a target total drug exposure ("area-under-the-curve" or AUC concentration) of 3,000 "nanogram-hours per milliliter" (ng-hr/mL) at the end of an 8-hour dosing interval, all 4 women had AUC concentrations were less than the target. The results showed wide inter-patient variability with a median SQV AUC of 1,672 ng-hr/mL (range of 738-2,614) and a median minimum (lowest) concentration of 60 ng/mL. One of five infants (note there was one set of twins) was HIV positive, even with continued dosing of anti-HIV drugs during labor and delivery. The authors concluded that the standard dosing produced saquinavir "exposure below that observed in non-pregnant adults" and that "may note be adequate for longer-term therapy." The phase I protocol called for modifying the dosing for the next 6 pregnant women if saquinavir levels were low, and "subsequent participants began therapy with saquinavir/ritonavir at 800/100 mg twice daily." The low levels of saquinavir might be due to altered metabolism associated with hormone changes during pregnancy itself or possibly due to the higher weight during pregnancy, or both.

Reference
Acosta EP and others. Pharmacokinetics of saquinavir-SGC in HIV-infected pregnant women. Abstract and poster presentation 3.8 at the 2nd International Workshop of Clinical Pharmacology of HIV Therapy; April 2-4, 2001; Noordwijk, the Netherlands.

Twice Daily Saquinavir As Either Fortovase or Invirase, with Ritonavir
Dr. Michael Kurowski of Auguste Viktoria Hospital in Berlin, Germany presented at equivalence study of saquinavir plus ritonavir (Norvir, PI drug). A twice-daily regimen of Fortovase (soft gel saquinavir) 1,000 mg plus ritonavir 100 mg was compared to twice-daily Invirase (hard gel original saquinavir) 1,000 mg plus ritonavir 100 mg. A total of 24 HIV positive patients were included in the cross-over study (patients in one regimen for at least 3 weeks, then crossed over to the other regimen for 10 days). The results showed that drug levels of saquinavir in the Invirase arm were comparable yet insignificantly lower than those of the Fortovase arm. Specifically, the minimum concentration after 12 hours was 14% lower and the total drug exposure ("area-under-the-curve") was 23% lower. However, the minimum concentration in all patients was significantly greater than the "EC50" (effective inhibitory concentration for 50% of HIV growth) of treatment-naïve (no previous treatment) patients. (One patient in the Invirase arm was close to the EC50). New adverse events were somewhat more common among those who switched to Fortovase (6 of 12) than among those who switched to Invirase (2 of 12) and were mostly gastro-intestinal (stomach-colon). Previously, all ritonavir-enhanced saquinavir regimens have been shown to have significantly higher drug levels of saquinavir than those of saquinavir (either Fortovase or Invirase) without ritonavir. Roche has remained committed to continuing manufacture of both formulations.

Reference
Kurowski M and others. Comparative pharmacokinetics of twice daily (BID) Fortovase/ritonavir and Invirase/ritonavir. Abstract and oral presentation 3.2 at the 2nd International Workshop of Clinical Pharmacology of HIV Therapy; April 2-4, 2001; Noordwijk, the Netherlands.

NIH Proposes New Drug Interaction Program and Information Resource
Representatives from the US National Institute of Health (NIH) proposed a new program that would expand research into anti-HIV drug interactions and provide a central information database about drug interactions. Drs. Jag Khalsa of the National Institute on Drug Abuse (NIDA), Kellie S. Reynolds of the Food and Drug Administration (FDA) and Karin Klingman of the National Institute of Allergy and Infectious Diseases (NIAID) each spoke at the Workshop. The program is being proposed due to the expanding number of drugs that many persons with HIV are taking, in addition to their anti-HIV regimen. Other drugs commonly used include those to treat: mental disorders (depression, psychosis [thought disorder], panic disorder, others), high cholesterol and/or triglycerides (blood fats), drug addiction (methadone, others), diabetes (high blood sugar), hypertension (high blood pressure), other (non-HIV) infections (antibacterial, antiviral, antiparasitic antibiotics), seizures (epilepsy, "fits"), erectile dysfunction, in addition to "natural" or "herbal" products that are available without prescription and recreational drugs.

The authors acknowledged, "People with HIV are being exposed to scores of multi-drug combinations that have never been clinically evaluated for safety or pharmacokinetic [drug level] interactions." And, "This not only puts patients at risk for adverse drug reactions but also has the effect of delaying much needed research on new combination therapies." The newly proposed project will address these issues and "fill a critical information gap."

The proposed project will have five basic objectives: (1) "gather and assess existing drug interaction data; (2) identify drug combinations of concern (especially [those combinations with at least] 3 drugs; (3) perform in vitro [laboratory] and/or animal screening tests and pharmacokinetic modeling; (4) conduct pharmacokinetic studies in adults and children…; and (5) recommend appropriate dose adjustments for adults and children." The doctors also proposed "providing support for 4-6 clinical safety/PK [drug interaction] studies per year that otherwise would not be done."

The proposed project also will "support a comprehensive information service to assist patients, pharmacists, and health-care providers…" This would include drug interaction information as well as relevant findings from the emerging field of "pharmacogenomics" (genetic basis for drug interactions and metabolism) and "neutraceuticals" (nutritional supplements with the potential for interactions with drugs).

The doctors asked attendees for their scientific input into their proposals regarding the scientific merit, potential obstacles, role of the pharmaceutical industry, and required level of support. Attendees may contact Dr. Jonathan Kagan at the NIAID (email: jkagan@niaid.nih.gov).

(Editorial note from Jules Levin: although this drug interaction project is just a proposal it is incumbant upon the NIH to undertake this initiative. This and a few additional needs should be addressed by the NIH. The NIH should initiate a project to explore HIV drug side effects and toxicities to a greater extent than is already done. The emergence of lipodystrophy and hepatotoxicity, and other unexpected side effects and toxicities call out for a comprehensive improved approach at collecting and analyzing this type of data. Since increasingly patients are finding they are coinfected with Hepatitis C and HIV, and coinfected persons wil be receiving treatment for HIV and HCV simultaneously, the NIH should initiate a project to collect potential drug-drug interaction, side effect and toxicity data that may result from being concurrent treatment for HCV and HIV).

Reference
Kagan J and others. HIV drug interaction research and information resource. Abstract and oral presentation 1.1 at the 2nd International Workshop of Clinical Pharmacology of HIV Therapy; April 2-4, 2001; Noordwijk, the Netherlands.

FDA Seeks Input into Draft Document for Pharmaceutical Companies
Drs. Kellie S. Reynolds and Kimberly Struble from the US FDA (Food and Drug Administration) authored a poster presentation about an upcoming draft document that will be sent to the pharmaceutical companies that have developed or are developing anti-HIV drugs. The FDA had convened an Advisory Committee to their Antiviral Drug Products division to address newer pharmacologic issues in the area of anti-HIV treatments. One main issue is the role of pharmacokinetics (drug levels, interactions) when evaluating newer formulations, alternative dosing and new combinations of FDA-approved anti-HIV drugs. One specific issue is the common, "off-label" practice of using ritonavir (Norvir, PI drug) to increase the drug levels of a second PI (protease inhibitor) drug ("pharmacologic enhancement"). Another major consideration by the FDA is relevant pharmacologic issues for heavily pretreated patients and children when considering trial design of new drugs. The abstract and poster presentation should be available at the website of the Workshop (www.HIVpharmacology.com or www.virology-education.com). The FDA authors seek comments (email to Reynoldsk@cder.fda.gov or Strubek@cder.fda.gov). Two members of the Organizing Committee of this Workshop were speakers at the Advisory Committee, including Richard M. W. Hoetelmans, PharmD, PhD of Virco and Terrence Blaschke, MD of Stanford University in California.

Reference
Reynolds KS and Struble K. The role of clinical pharmacology, efficacy and safety data in the developments of antiretroviral agents. Abstract and poster presentation 3.6 at the 2nd International Workshop of Clinical Pharmacology of HIV Therapy; April 2-4, 2001; Noordwijk, the Netherlands.