Time-Dependent Interaction of Ritonavir in Chronic Use: The Power Balance Between Inhibition and Induction of P-Glycoprotein and Cytochrome P450 3A

Fukushima, Keizo; Kobuchi, Shinji; Mizuhara, Kazunori; Aoyama, Hiroaki; Takada, Kanji; Sugioka, Nobuyuki

doi:10.1002/jps.23545

Cited by 12 publications

(14 citation statements)

References 27 publications

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“…[8][9][10][11] Ritonavir is a potent inhibitor and/or inducer of CYP3A4 and several membrane transporter proteins. [16][17][18][22][23][24] CYP3A4 inhibition by LPV/r results in a higher concentration of the antimalarial lumefantrine (2-to 3-fold increase in systemic exposure) in healthy subjects, 25 and was associated with lower incidence of malaria and longer posttreatment prophylaxis. 26 Inhibition of CYP3A4-mediated metabolism of quinine may result in toxic quinine plasma concentrations, leading to risk of toxicity or untoward side effects.…”

Section: Introductionmentioning

confidence: 99%

“…52 A recent randomized study comparing treatment with nevirapine versus LPV/r in HIV-infected children in sub-Saharan Africa found that patients in the nevirapine arm had a significantly higher risk of developing malaria. 24 High plasma protein binding of both lopinavir and ritonavir and lack of information on their penetration into red cells suggests that further work is required to establish the clinical relevance of these findings. The more favorable drug interaction profile of the LPV/r arm and potential antimalarial activity of this protease inhibitor may have contributed to this effect.…”

mentioning

confidence: 99%

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Pharmacokinetic Interactions Between Quinine and Lopinavir/Ritonavir in Healthy Thai Adults

Rattanapunya¹,

Cressey²,

Rueangweerayut³

et al. 2015

The American Society of Tropical Medicine and Hygiene

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Abstract. This study aimed to investigate the pharmacokinetic interactions between quinine and lopinavir boosted with ritonavir (LPV/r) in healthy Thai adults (8 males and 12 females). Period 1 (day 1): subjects received a single oral dose of 600 mg quinine sulfate. Period 2: subjects received LPV/r (400/100 mg) twice daily. Period 3: subjects received a single quinine sulfate dose plus LPV/r twice a day. Intensive blood sampling was performed during each phase. Quinine AUC 0-48h (area under the plasma concentration-time curve from time 0 to 48 hours), AUC 0-∞ (area under the plasma concentration-time curve from time 0 to infinity), and C max (maximum concentration over the time-span specified), were 56%, 57%, and 47% lower, respectively, in the presence of LPV/r. 3-Hydroxyquinine AUC 0-48h , AUC 0-∞ , and C max were significantly lower and the metabolite-to-parent ratio was significantly reduced. Lopinavir and ritonavir exposures were not significantly reduced with quinine coadministration, but C max of both drugs were significantly lower. The geometric mean ratio (GMR) and 90% CI of AUC 0-48h , AUC 0-∞ , and C max for quinine, 3-hydroxyquinine, lopinavir, and ritonavir lay outside the bioequivalent range of 0.8-1.25. Drug treatments during all periods were generally well tolerated. The reduction in systemic exposure of quinine and 3-hydroxyquinine with concomitant LPV/r use raises concerns of suboptimal exposure. Studies in HIV/malaria coinfection patients are needed to determine the clinical impact to decide if any change to the quinine dose is warranted.

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Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

Pharmacokinetic Interactions Between Quinine and Lopinavir/Ritonavir in Healthy Thai Adults

Rattanapunya¹,

Cressey²,

Rueangweerayut³

et al. 2015

The American Society of Tropical Medicine and Hygiene

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“…This could explain why lower platelet inhibition was observed by Hauguel-Moreau et al in HIV patients compared with non-HIV patients. Potent inhibition of the CYP3A enzyme by ritonavir has been the subject of numerous in vitro and in vivo studies [6,7,24,25]. A few studies suggested that ritonavir could also induce CYP3A when administered at steady state, but all these studies were conducted in rats [25][26][27].…”

Section: Discussionmentioning

confidence: 99%

Impact of Boosted Antiretroviral Therapy on the Pharmacokinetics and Efficacy of Clopidogrel and Prasugrel Active Metabolites

et al. 2018

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“…For example, the PIs amprenavir, fosamprenavir, and tipranavir have been shown to induce pgp. Similar to ritonavir's boosting effect secondary to CYP inhibition, in animal models, ritonavir increased drug absorption via inhibition of pgp transport proteins in the GI tract [9]. As a result, the concentration of digoxin, a pgp substrate, was increased by 29 % with ritonavir co-administration.…”

Section: Antiretroviral Therapy and Cytochrome P450mentioning

confidence: 95%

A Review of the Toxicity of HIV Medications II: Interactions with Drugs and Complementary and Alternative Medicine Products

et al. 2015

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For many patients today, HIV has become a chronic disease. For those patients who have access to and adhere to lifelong antiretroviral (ARV) therapy, the potential for drugdrug interactions has become a real and life-threatening concern. It is known that most ARV drug interactions occur through the cytochrome P450 (CYP) pathway. Medications for comorbid medical conditions, holistic supplements, and illicit drugs can be affected by CYP inhibitors and inducers and have the potential to cause harm and toxicity. Protease inhibitors (PIs) tend to inhibit CYP3A4, while most nonnucleoside reverse transcriptase inhibitors (NNRTIs) tend to induce the enzyme. As such, failure to adjust the dose of coadministered medications, such as statins and steroids, may lead to serious complications including rhabdomyolysis and hypercortisolism, respectively. Similarly, gastric acid blockers can decrease several ARV absorption, and warfarin doses may need to be adjusted to maintain therapeutic concentrations. Illicit drugs such as methylenedioxymethamphetamine (MDMA, "ecstasy") in combination with PIs lead to increased toxicity, while the concomitant administration of sedative drugs such as midazolam and alprazolam in patients taking PIs can result in prolonged sedation, delayed recovery, and increased length of stay. Even supplements like St. John's Wort can alter PI concentrations. In theory, any drug that is metabolized by CYP has potential for a pharmacokinetic drug-drug interaction with all PIs, cobicistat, and most NNRTIs. When adding a new medication to an ARV regimen, use of a drug-drug interaction software and/or consultation with a clinical pharmacist/pharmacologist or HIV specialist is recommended.

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Time-Dependent Interaction of Ritonavir in Chronic Use: The Power Balance Between Inhibition and Induction of P-Glycoprotein and Cytochrome P450 3A

Cited by 12 publications

References 27 publications

Pharmacokinetic Interactions Between Quinine and Lopinavir/Ritonavir in Healthy Thai Adults

Pharmacokinetic Interactions Between Quinine and Lopinavir/Ritonavir in Healthy Thai Adults

Impact of Boosted Antiretroviral Therapy on the Pharmacokinetics and Efficacy of Clopidogrel and Prasugrel Active Metabolites

A Review of the Toxicity of HIV Medications II: Interactions with Drugs and Complementary and Alternative Medicine Products

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