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John G. Gerber - One of the best experts on this subject based on the ideXlab platform.
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Pharmacokinetic interactions between Indinavir Plus Ritonavir and calcium channel blockers.
Clinical pharmacology and therapeutics, 2005Co-Authors: Marshall J. Glesby, Judith A. Aberg, Michelle A. Kendall, Carl J. Fichtenbaum, Richard Hafner, Stephen D. Hall, Nicole Grosskopf, Andrew R. Zolopa, John G. GerberAbstract: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. Clinical Pharmacology & Therapeutics (2005) 78, 143–153; doi: 10.1016/j.clpt.2005.04.005
Marshall J. Glesby - One of the best experts on this subject based on the ideXlab platform.
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Pharmacokinetic interactions between Indinavir Plus Ritonavir and calcium channel blockers.
Clinical pharmacology and therapeutics, 2005Co-Authors: Marshall J. Glesby, Judith A. Aberg, Michelle A. Kendall, Carl J. Fichtenbaum, Richard Hafner, Stephen D. Hall, Nicole Grosskopf, Andrew R. Zolopa, John G. GerberAbstract: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. Clinical Pharmacology & Therapeutics (2005) 78, 143–153; doi: 10.1016/j.clpt.2005.04.005
Michel Tod - One of the best experts on this subject based on the ideXlab platform.
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Extreme bradycardia due to multiple drug-drug interactions in a patient with HIV post-exposure prophylaxis containing lopinavir-Ritonavir.
British journal of clinical pharmacology, 2011Co-Authors: Rachel Puech, Marie-claude Gagnieu, Caroline Planus, B. Charpiat, André Boibieux, Tristan Ferry, Michel TodAbstract:We report a case of an extreme bradycardia in a cardiac patient, due to multiple drug–drug interactions. This case caused significant diagnostic problems and illustrates the interplay between pharmacokinetics and pharmacogenetics. A 51-year-old man with a history of hypertensive and ischaemic myocardiopathy (cardiac infarction 11 years ago), osteoarthritis and hypothyroidism, was treated daily with lacidipine 2 mg, ramipril 5 mg, levothyroxine 75 µg, rosuvastatin 20 mg, metoprolol 100 mg and acetylsalicylic acid 325 mg. The patient consulted after a possible exposure to HIV during unsafe sexual activity. The physician prescribed a post-exposure prophylaxis (PEP) containing tenofovir disoproxil fumarate 245 mg/emtricitabine 200 mg combination once daily Plus lopinavir 400 mg/Ritonavir 100 mg combination twice daily for 1 month. Forty-eight hours after starting PEP, the patient presented a vasovagal syncope with severe hypotension (blood pressure was 50/20 mmHg) and extreme bradycardia (20–25 beats min−1). An electrocardiogram showed complete atrioventricular block (AV). The patient recovered a regular sinus rhythm after treatment with isoprenaline. Results of all diagnostic tests, including cardiac enzymes, complete blood cell count, electrolytes and tomodensitometry were normal. Lopinavir/Ritonavir, lacidipine, ramipril and metoprolol were discontinued. Raltegravir was prescribed on day 4. Lacidipine, ramipril were re-instated on day 7 and metoprolol on day 9. We suspected the involvement of multiple drug–drug interactions between Ritonavir and metoprolol and/or lacidipine. Lopinavir, Ritonavir, tenofovir and emtricitabine were quantified by high-performance liquid chromatography. The subject was genotyped for several allelic variants most commonly found in Caucasians. The genes CYP2D6, CYP3A4, CYP3A5 and ABCB1 were amplified to detect 26 single nucleotide polymorphisms on CYP2D6, the CYP3A5*3 alleles, the −392A>G variant on CYP3A4 and the variants 1236C>T on exon 12, 2677 G > T/A on exon 21, and 3435 C > T on exon 26 on ABCB1. CYP2D6 deletion and gene duplication were also assessed. Blood concentrations were analyzed approximately 12 h after the last dose of tenofovir/emtricitabine combination and 20 h after the last dose of lopinavir/Ritonavir combination. Lopinavir, Ritonavir, tenofovir and emtricitabine plasma concentrations were 8.40 mg l−1, 0.29 mg l−1, 0.059 mg l−1 and 0.12 mg l−1, respectively. The lopinavir plasma concentration was higher than usual (3 to 7 mg l−1); but the measurement was done only 3 days after treatment initiation while 2 weeks are required to see the maximal enzyme inducing effects of Ritonavir. Tenofovir and emtricitabine plasma concentrations were in the normal range. The patient carried CYP2D6*4/*2 alleles. No duplication of the CYP2D6 gene was found. The patient was classified as an intermediate metabolizer of CYP2D6. He had no potential functional alteration of CYP3A as the CYP3A4*1B polymorphism was not found, and CYP3A5 was not expressed (*3/*3). The patient appeared to be a CYP3A normal metabolizer. He was homozygous for the haplotype 2677T, 1236T and 3435T on ABCB1. This haplotype TTT is associated with lower ABCB1 expression. The AV block and hypotension in this case is consistent with an overexposure to metoprolol and lacidipine. This overexposure may be due to multiple pharmacokinetic interactions with the protease inhibitors Ritonavir and lopinavir and/or to genetic polymorphism. Metoprolol undergoes α-hydroxylation and O-demethylation by several CYPs (predominantly 2D6 but also 3A4) [1]. Ramipril is hydrolyzed by esterases to ramiprilat, which is glucuronoconjugated [2]. Lacidipine is oxidized to pyridine derivatives by CYP3A4 [3]. We have several reasons to conclude that the AV block and the hypotension in this case was primarily associated with co-administration of the lopinavir/Ritonavir combination with metoprolol and lacidipine. First, the patient was asymptomatic while he started antiretroviral therapy. Second, discontinuation of lopinavir/Ritonavir, lacidipine, ramipril and metoprolol, restored normal rhythm. Third, the re-introduction of lacidipine, ramipril and metoprolol without lopinavir/Ritonavir induced no bradyarrythmia. So, the antiprotease combination might have induced a drug–drug interaction and consequently a disruption in the treatment. Ritonavir is a potent inhibitor of CYP3A4 and to a lesser extent, of CYP2D6. Ritonavir exerts a complex dose and time dependent inhibitory/induction effect on CYP3A and on the multidrug efflux P-glycoprotein (P-gp) [4]. It exerts a moderate dose-related inhibition of CYP2D6 [5]. Lopinavir is a substrate of CYP3A, P-gp and to a lesser extent CYP2D6 [6]. Metoprolol, a selective β1-adrenoceptor antagonist, undergoes significant first pass metabolism with approximately 85% of the dose converted mainly into an inactive metabolite via CYP2D6 in extensive metabolizers. Finally, lacidipine (a dihydropyridine calcium antagonist) is a CYP3A4 substrate. Because lacidipine is a P-gp inhibitor [7], it is also possibly a substrate of P-gp. Even though the Ritonavir-metoprolol interaction has never been studied, a possible increase in the average plasma exposure to metoprolol is supported by theoretical considerations and several case reports [8–10]. One of these described a complete AV block with metoprolol after co-administration of paroxetine, another CYP2D6 inhibitor [5]. The in vitro Ki of Ritonavir for CYP2D6 is 2.5 mg l−1[11], which is higher than the Ritonavir concentration measured in plasma (0.3 mg l−1). Nevertheless, it has been shown that low-dose Ritonavir (100 mg twice daily) increased desipramine (a substrate of CYP2D6) AUC by 1.26 [12]. Because the contribution of CYP2D6 to total clearance is similar for desipramine and metoprolol (fm = 0.85) [13], the same degree of interaction is expected. In addition, metoprolol is metabolized by CY3A4. Because the patient was an intermediate metabolizer for CYP2D6, the contribution of CYP3A4 to the total clearance of metoprolol was increased. The in vitro Ki of Ritonavir for CYP3A4 is 0.05 mg l [11]. Hence inhibition of CYP3A4 by low dose Ritonavir might have contributed to an increased metoprolol exposure. Co-administration of Ritonavir with lacidipine, whose bioavailability is less than 50% [14], may increase exposure to lacidipine by inhibiting CYP3A4 and P-gp, resulting in hypotension. Although this interaction has only a theoretical basis, it is well described with other dihydropyridine calcium antagonists. The co-administration of nifedipine with Ritonavir may significantly increase nifedipine exposure, resulting in toxicity [15]. Indinavir Plus Ritonavir increases the AUC of amlodipine [16]. A case of symptomatic orthostasis and heart block after starting antiretroviral therapy that included nelfinavir was reported in a man who was receiving extended release nifedipine [17]. From a pharmacogenetic point of view, the patient was an extensive metabolizer for CYP3A and low expressor of P-gp. The TTT haplotype found in this patient is associated with higher plasma concentrations of P-gp substrates leading to a potential increase of lacidipine bioavailability without an increase in its metabolism because of the CYP3A5 genotype [18]. This case raises several important points. Firstly, HIV PEP has a strong potential for drug–drug interactions in patients with comorbidities requiring long term medications. Secondly, as illustrated by our case report, these potential interactions have to be identified as they may lead to early near-fatal complications. Systematic pharmacogenetic analyses combined with pharmaceutical analysis of the prescriptions may help in understanding, forecasting and managing these interactions.
Carl J. Fichtenbaum - One of the best experts on this subject based on the ideXlab platform.
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Pharmacokinetic interactions between Indinavir Plus Ritonavir and calcium channel blockers.
Clinical pharmacology and therapeutics, 2005Co-Authors: Marshall J. Glesby, Judith A. Aberg, Michelle A. Kendall, Carl J. Fichtenbaum, Richard Hafner, Stephen D. Hall, Nicole Grosskopf, Andrew R. Zolopa, John G. GerberAbstract: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. Clinical Pharmacology & Therapeutics (2005) 78, 143–153; doi: 10.1016/j.clpt.2005.04.005
Stephen D. Hall - One of the best experts on this subject based on the ideXlab platform.
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Pharmacokinetic interactions between Indinavir Plus Ritonavir and calcium channel blockers.
Clinical pharmacology and therapeutics, 2005Co-Authors: Marshall J. Glesby, Judith A. Aberg, Michelle A. Kendall, Carl J. Fichtenbaum, Richard Hafner, Stephen D. Hall, Nicole Grosskopf, Andrew R. Zolopa, John G. GerberAbstract: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. Clinical Pharmacology & Therapeutics (2005) 78, 143–153; doi: 10.1016/j.clpt.2005.04.005