Drug Interactions

Drug Interactions    46th ICAAC    45th ICAAC    12th Conference on Retroviruses and Opportunistic Infections (12th CROI)    43rd Annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC)    IAS 2003 (International AIDS Society 2003)    10th Conference on Retroviruses and Opportunistic Infections    43rd Annual International Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL.    Drug-Drug Interaction abstracts presented at 10th Conference on Retrovirus and Opportunistic Infections, Boston, MA - Feb. 10-14, 2003    Drug-Drug Interaction abstracts presented at 4th International Workshop on Clinical Pharmacology of HIV Therapy, Cannes, France, March 27-29, 2003     NOTE: Some of these links require a free registration with Medscape.    Use of Complementary Medicines by Patients With HIV: Full Sail Into Uncharted Waters    APHA 2000 – Drug Interactions: Decreasing the Risk    Drug Interactions and Pharmacology: Better Understanding of Present and Future Antiretroviral Therapy    Clinical Significance of Antiretroviral Drug Levels

Robert DiCenzo, Pharm.D.

Department of Pharmacy Practice
School of Pharmacy and Pharmaceutical Sciences
University at Buffalo
E-mail: robert_dicenzo@urmc.rochester.edu

Page Contents Antiretroviral and dietary supplement drug interaction studies  Potential benefit of adding an additional dose of ritonavir (RTV) to a "dual boosted" protease inhibitor regimen.  The PK of Fortovase (SQV) when combined with Kaletra (LPV/r) in healthy subjects at steady state.  Indinavir and ritonavir concentrations are lower when combined with efavirenz  Interactions between antiretroviral agents & alternative therapies  Interactions between SSRIs and antiretroviral therapy  Interactions between antifungal medications and antiretroviral therapy  Publications Considered Essential for Reading  Abstracts

Siberian ginseng extracts are unlikely to alter the disposition of co-administered medications that are metabolized via CYP2D6 and CYP3A4. Read more...

Raguin and colleagues presented data at the 42 ICAAC that supports adding an additional 200mg of RTV to lopinavir/ritonavir (LPV/RTV) + amprenavir (APV). In this multicenter randomized trial, 37 PI and NNRTI experienced patients received LPV/RTV + APV with or without an additional 200mg dose of RTV. Although pharmacokinetic results were not shown, changes in plasma HIV-1 RNA levels were significantly greater at week 26 in the group that received an additional dose of RTV. There was no difference in tolerability or adverse events. These results support the addition of RTV when using a LPV/RTV + APV based regimen. Further study including pharmacokinetic exposure parameters, such as trough concentrations, are necessary.

Bertz et al looked at the effect of LPV/r 400/100mg BID on the PK of SQV and IDV in healthy subjects.

SQV 1200mg TID alone (Days 1-5) was compared to SQV 800mg BID + LPV 400/100mg BID (Days 5-15) and SQV 1200mg BID + LPV 400/100mg BID (Days 15-20). PK sampling was performed on Days 5, 15, and 20.

SQV C_max, C_min, C_trough, AUC, t 1/2, and IQ were significantly higher for both combination regimens compared to SQV 1200mg TID. When combining the data for both the 800 and 1200mg BID regimens, the ratio of SQV + LPV/r / SQV alone for SQV AUC24 = 9.6 and C_min = 16.7, and the SQV median IQ increased from 0.27 to 5.2.

SQV concentrations were found to be similar for both the SQV 800mg and 1200mg BID + LPV 400/100mg BID combination regimens. Ratio (90% CI) for both C_max and AUC = 1.00 (0.82, 1.23) and C_min = 1.04 (0.82, 1.32).

They conclude that SQV C_min was 16.7 times higher during SQV 800mg BID + LPV/r compared to SQV 1200mg TID alone and that SQV 1200mg BID and 800mg BID + LPV/r produced similar SQV concentrations and that lower SQV dosing regimens are being explored.

When the concept of dual PI was first introduced one of the many logical assumptions made was that the effect of cytochrome P-450 (CYP3A4) inducing agents; such as efavirenz, would be blunted in the presence of a CYP3A4 inhibitor; such as ritonavir.

Aarnoutse and colleagues studied the effect of efavirenz on IDV 800mg plus RTV 100mg twice daily for two weeks and found a significant decrease in IDV exposure: area under the concentration-time curve decreased by 25% (p<0.01).

The authors also noted that even though the IDV trough concentrations were decreased, they still remained the same or above those achieved when IDV 800mg was given three times a day without RTV.

Results of this and similar trials point to the need for clinical trials that identify the impact that lower exposure to PI will have an therapeutic outcome. Also, these results further underline the potential value of therapeutic drug monitoring in the face of the complex and unpredictable drug interactions seen in antiretroviral therapy.

Clin Pharmacol Ther 2002;71:57-67.

A 3 period, two week, open-label, fixed schedule (300mg TID) study using a drug probe cocktail to determine the effect of St John's wort on cytochrome P450 enzyme activity in... (Read More)

Interactions between SSRIs and antiretroviral therapy

Summary of Abstract Info: Five case studies of HIV-positive patients who were receiving antiretroviral therapy and antidepressants and presented with symptoms consistent with serotonin syndrome. Antidepressant medications were either discontinued or doses were decreased in order to resolve the symptoms. (Read More)

Summary of Abstract Info: Five subjects treated with saquinavir (1200 mg TID) and three with ritonavir (600 mg BID), were first given the protease inhibitor alone on day one, then in combination with fluconazole on days 2 thru 8 (400 mg on day 2, 200 mg on days 3 thru 8). (Read More)

Publications Considered Essential for Reading

1. Morse, GD. Drug Interactions with Antiretrovirals. Current Infectious Disease Reports 2000; Jun 2(3):257-266. [PubMed]

2. Piscitelli SC, Burstein AH, Chaitt D, Alfaro RM, Falloon J. Indinavir concentrations and St John’s wort [letter]. Lancet 2000; 355(9203): 547-8. [PubMed]

3. Barry M, Mulcahy F, Concepta M, Gibbons S, Back D. Pharmacokinetics and potential interactions amongst antiretroviral agents used to treat patients with HIV infection. Clin Pharmacokinet 1999; 36(4): 289-304. [PubMed]

4. Pharm PA, Flexner C, Antiretroviral drug interactions in the HIV-infected patient. HIV Advances in Research and Therapy. 1997; 7(2):10-17.

5. Kim RB, Fromm MF, Wandel C, Leake B, Wood AJJ, Roden DM, et al. The drug transporter P-glycoprotein limits oral absorption and brain entry of protease inhibitors. J Clin Invest 1998;101: 289-294. [PubMed]

1. Sadler et al. Pharmacokinetic Drug-Interaction between Amprenavir and Ritonavir in HIV-seronegative subjects after multiple, oral dosing [abstract 77]. 7th Conference on Retrovirus and Opportunistic Infections. 2000 Jan 30 – Feb 2; San Francisco, CA.

2. Piscitelli SC, Bechtel C, Sadler B, Falloon J, and the Intramural AIDS Program. NIH Bethesda, MD, and Glaxo Wellcome, Res. Triangle Park, NC. The addition of a second protease inhibitor eliminates amprenavir-efavirenz drug interactions and increases plasma amprenavir concentrations [abstract 78]. 7th Conference on Retrovirus and Opportunistic Infections. 2000 Jan 30 – Feb 2; San Francisco, CA.

3. Clarke S, Mulcahy F, Back D, Gibbons S, Tjia J, Barry M. Managing methadone and non-nucleoside reverse transcriptase inhibitors: Guideline for clinical practice [abstract 88]. 7th Conference on Retrovirus and Opportunistic Infections. 2000 Jan 30 – Feb 2; San Francisco, CA.

4. Flexner C. Dual protease inhibitor therapy in HIV-infected patients: pharmacologic rationale and clinical benefits. Annual Review of Pharmacology and Toxicology 2000; 40:649-674. [PubMed]

5. Gerber JG. Using pharmacokinetics to optimize antiretroviral drug-drug interactions in the treatment of human immunodeficiency virus infection. Clinical Infectious Diseases 2000;30 Suppl 2: S123-S129. [PubMed]

6. Schuetz EG and Schinkel AH. Drug disposition as determined by the interplay between drug-transporting and drug-metabolizing systems. J Biochem Molecular Toxiciology 1999;13:219-222.

7. Huisman MT, Smit JW,and Schinkel AH. Significance of P-glycoprotein for the pharmacology and clinical use of HIV protease inhibitors. AIDS 2000;14:237-242.

8. Sadeque AJ, Wandel C, He H, Shah S and Wood AJ. Increased drug delivery to the brain by P-glycoprotein inhibition. Clinical Pharmacology & Therapeutics 2000;68-231-237. [PubMed]

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