Lopinavir/ritonavir significantly influences pharmacokinetic exposure of artemether/lumefantrine in HIV-infected Ugandan adults

Byakika-Kibwika, Pauline; Lamorde, Mohammed; Okaba-Kayom, Violet; Mayanja‐Kizza, Harriet; Katabira, Elly; Hanpithakpong, Warunee; Pakker, Nadine; Dorlo, Thomas P. C.; Tärning, Joel; Lindegårdh, Niklas; Vries, Peter J. de; Back, David; Khoo, Saye; Merry, Concepta

doi:10.1093/jac/dkr596

Cited by 44 publications

(44 citation statements)

References 36 publications

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“…Steady-state ritonavir-lopinavir decreased hepatic CYP3A activity by 77%, whereas hepatic CYP1A2, CYP2C9, and CYP2C19 activities increased by 43%, 29%, and 100% (Yeh et al, 2006). Ritonavir-lopinavir inhibited CYP3A-dependent elimination of lumefantrine while concurrently inducing metabolism of artemether, attributed to induction of CPY2B6, CYP2C9, or CYP2C19 (Byakika-Kibwika et al, 2012). More specifically, and of particular pertinence to this investigation, is that ritonavir-lopinavir inhibits CYP3A while significantly inducing hepatic CYP2B6 activity (Piscitelli et al, 2000;Hogeland et al, 2007).…”

Section: Controlmentioning

confidence: 73%

Cytochrome P4503A Does Not Mediate the Interaction between Methadone and Ritonavir-Lopinavir

Kharasch

Stubbert

2013

Drug Metab Dispos

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Plasma concentrations of orally administered methadone are reduced by the human immunodeficiency virus protease inhibitor combination ritonavir and lopinavir, but the mechanism is unknown. Methadone metabolism, clearance, and drug interactions have been attributed to CYP3A4, but this remains controversial. This investigation assessed the effects of acute (2 days) and steady-state (2 weeks) ritonavirlopinavir on intravenous and oral methadone metabolism and clearance, hepatic and intestinal CYP3A4/5 activity (using the probe substrate intravenous and oral alfentanil), and intestinal transporter activity (using oral fexofenadine) in healthy volunteers. Plasma and urine concentrations of methadone and metabolite enantiomers, and other analytes, were determined by mass spectrometry. Acute and chronic ritonavir-lopinavir reduced plasma methadone enantiomer concentrations in half, with an average 2.6-and 1.5-fold induction of systemic and apparent oral methadone clearances. Induction was attributable to stereoselectively increased hepatic methadone N-demethylation, hepatic extraction, and hepatic clearance, and there was a strong correlation between methadone N-demethylation and clearance. Methadone renal clearance was unchanged. Alfentanil's systemic clearance and hepatic extraction, apparent oral clearance, and intestinal extraction were reduced to 25%, 16%, and 35% of control, indicating strong inhibition of hepatic and intestinal CYP3A activities. Ritonavir-lopinavir (acute > chronic) increased fexofenadine exposure, suggesting intestinal P-glycoprotein inhibition. No correlation was found between methadone clearance and CYP3A activity. Acute and steady-state ritonavir-lopinavir stereoselectively induced methadone N-demethylation and clearance, despite significant inhibition of hepatic and intestinal CYP3A activity. Ritonavir-lopinavir inhibited intestinal transporters activity but had no effect on methadone bioavailability. These results do not support a significant role for CYP3A or ritonavir-lopinavir-inhibitable intestinal transporters in single-dose methadone disposition.

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Section: Controlmentioning

confidence: 73%

Cytochrome P4503A Does Not Mediate the Interaction between Methadone and Ritonavir-Lopinavir

Kharasch

Stubbert

2013

Drug Metab Dispos

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“…6,7 There is accumulating evidence suggesting clinically important drug-drug interactions occur between antimalarial and antiretroviral drugs, which could potentially affect treatment efficacy and/or tolerability. [8][9][10][11] Quinine is the first-line antimalarial drug recommended by the World Health Organization (WHO) for treatment of pregnant women with uncomplicated P. falciparum malaria during the first trimester as 7-day quinine-clindamycin combination. In addition, it is the second-line treatment of severe P. falciparum malaria in most endemic areas.…”

Section: Introductionmentioning

confidence: 99%

“…[16][17][18][19][20][21] Elimination halflives of quinine, lopinavir, and ritonavir are in the ranges of 9-15, 6-14, and 3-8 hours, respectively. [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.…”

Section: Introductionmentioning

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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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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“…An approximately twofold rise in AUC was reported in healthy volunteers who were given lumefantrine with lopinavir/ritonavir,[25] or darunavir/ritonavir[28] and this was confirmed in HIV positive (but malaria negative) patients (lumefantrine AUC increased between 3-fold and 5-fold, 7 day lumefantrine concentration increased up to 10-fold, when compared to ARV naive patients, or those with an EFV-containing regimen). [29, 30] Paediatric patients, but not adults, were found to experience increased adverse events when taking lumefantrine with LPV/r. [31] No change in ECG parameters were observed despite the significantly increased exposure, during single dosing, or a standard six dose regimen.…”

Section: Resultsmentioning

confidence: 99%

Development of an evidence evaluation and synthesis system for drug-drug interactions, and its application to a systematic review of HIV and malaria co-infection

et al. 2017

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BackgroundIn all settings, there are challenges associated with safely treating patients with multimorbidity and polypharmacy. The need to characterise, understand and limit harms resulting from medication use is therefore increasingly important. Drug-drug interactions (DDIs) are prevalent in patients taking antiretrovirals (ARVs) and if unmanaged, may pose considerable risk to treatment outcome. One of the biggest challenges in preventing DDIs is the substantial gap between theory and clinical practice. There are no robust methods published for formally assessing quality of evidence relating to DDIs, despite the diverse sources of information. We defined a transparent, structured process for developing evidence quality summaries in order to guide therapeutic decision making. This was applied to a systematic review of DDI data with considerable public health significance: HIV and malaria.Methods and findingsThis was a systematic review of DDI data between antiretrovirals and drugs used in prophylaxis and treatment of malaria. The data comprised all original research in humans that evaluated pharmacokinetic data and/or related adverse events when antiretroviral agents were combined with antimalarial agents, including healthy volunteers, patients with HIV and/or malaria, observational studies, and case reports. The data synthesis included 36 articles and conference presentations published via PubMed and conference websites/abstract books between 1987-August 2016. There is significant risk of DDIs between HIV protease inhibitors, or NNRTIs and artemesinin-containing antimalarial regimens. For many antiretrovirals, DDI studies with antimalarials were lacking, and the majority were of moderate to very low quality. Quality of evidence and strength of recommendation categories were defined and developed specifically for recommendations concerning DDIs.ConclusionsThere is significant potential for DDIs between antiretrovirals and antimalarials. The application of quality of evidence and strength of recommendation criteria to DDI data is feasible, and allows the assessment of DDIs to be robust, consistent, transparent and evidence-based.

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Lopinavir/ritonavir significantly influences pharmacokinetic exposure of artemether/lumefantrine in HIV-infected Ugandan adults

Cited by 44 publications

References 36 publications

Cytochrome P4503A Does Not Mediate the Interaction between Methadone and Ritonavir-Lopinavir

Cytochrome P4503A Does Not Mediate the Interaction between Methadone and Ritonavir-Lopinavir

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

Development of an evidence evaluation and synthesis system for drug-drug interactions, and its application to a systematic review of HIV and malaria co-infection

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