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Published on: October 18, 2018
Pharmacokinetic interactions between indinavir plus ritonavir and calcium channel blockers
Marshall J Glesby1, Judith A Aberg, Michelle A Kendall
1Weill Medical College of Cornell University, New York, NY 10021, USA. mag2005@med.cornell.edu
Insights
HIV protease inhibitors indinavir and ritonavir increase calcium channel blocker levels. Diltiazem and amlodipine doses should be started low and carefully adjusted to avoid side effects in patients taking these medications.
Area of Science:
- Pharmacology
- Drug Interactions
- Cardiovascular Medicine
Background:
- Hypertension is a significant cardiac risk factor in HIV-infected patients.
- Calcium channel blockers (CCBs) are commonly used for hypertension and are metabolized by cytochrome P450 3A.
- Potential pharmacokinetic interactions between CCBs and HIV protease inhibitors (indinavir and ritonavir) require investigation.
Purpose of the Study:
- To evaluate the bidirectional pharmacokinetic interactions between CCBs (amlodipine and diltiazem) and coadministered indinavir and ritonavir in healthy subjects.
Main Methods:
- Healthy, HIV-seronegative subjects received daily amlodipine or diltiazem.
- Subjects were coadministered indinavir and ritonavir.
- Pharmacokinetic parameters, including area under the curve (AUC), were measured at specific time points.
Main Results:
- Indinavir plus ritonavir significantly increased amlodipine AUC by 89.8% and diltiazem AUC by 26.5%.
- Metabolite AUCs of diltiazem also changed, with desacetyldiltiazem increasing and desmethyldiltiazem decreasing.
- No significant impact of amlodipine or diltiazem on the steady-state AUCs of indinavir and ritonavir was observed. No serious cardiovascular adverse events occurred.
Conclusions:
- Coadministration of indinavir plus ritonavir with amlodipine or diltiazem leads to increased CCB exposure.
- This interaction may enhance CCB response and potential side effects.
- Initiate CCBs at low doses and titrate carefully when used with indinavir and ritonavir.
Background:
Hypertension is an important modifiable cardiac risk factor in human immunodeficiency virus (HIV)-infected patients. Calcium channel blockers are substrates of cytochrome P450 3A and are commonly prescribed for hypertension. We evaluated potential bidirectional pharmacokinetic interactions between calcium channel blockers and coadministered indinavir and ritonavir.
Methods:
Healthy HIV- seronegative subjects received 120 mg diltiazem daily or 5 mg amlodipine daily for days 1 to 7 and 20 to 26. All subjects received 100 mg ritonavir and 800 mg indinavir every 12 hours on days 8 to 26. Twenty-four-hour pharmacokinetic collection was performed on days 7 and 26, with 12-hour collection on day 19.
Results:
Indinavir plus ritonavir increased the median amlodipine area under the curve from 0 to 24 hours (AUC) by 89.8%, from 122 to 230 ng.h/mL (n = 18, P < .0001), and increased the median diltiazem AUC by 26.5%, from 800 to 1060 ng.h/mL (n = 13, P = .06). Of 13 subjects, 2 (15%) had greater than 4-fold increases in diltiazem AUC. Desacetyldiltiazem AUC increased by 102.2% (P = .001), and desmethyldiltiazem AUC decreased by 27.4% (P = .01). Neither amlodipine nor diltiazem affected steady-state AUCs of the protease inhibitors. No serious cardiovascular adverse effects were observed.
Conclusions:
Indinavir plus ritonavir increases the AUCs of both amlodipine and diltiazem, which may result in an increased response. If coadministration is indicated, amlodipine or diltiazem should be initiated at low doses with careful titration to response and side effects.
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