Clinical pharmacology of the HIV integrase inhibitor raltegravir: drug-drug interactions and pharmacokinetics

Contains fulltext : 156498.pdf (publisher's version ) (Open Access)RU Radboud Universiteit, 22 april 2016Promotor : Burger, D.M.213 p

Les premiers équipements sportifs à La Réunion : une politique de l'Etat (1956-1971)

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Use of oral ketamine in chronic pain management: A review

The analgesic effect of ketamine is primarily based on the antagonism of the N-methyl-D-aspartate (NMDA) receptor. Activation of NMDA receptors may play a crucial role in the pathogenesis of chronic pain. Little formal research has been performed on the efficacy and safety of ketamine in chronic pain, especially concerning long-term oral administration. This review provides an overview of the available clinical data on the use of oral ketamine in chronic pain management. A literature search was performed in MEDLINE, EMBASE and the Cochrane Library, resulting in 22 relevant articles. Because most retrieved articles were of a descriptive nature (e. g. case reports and case series) a quantitative analysis was not possible. There was no consistent dose-response relation. A recommended starting dosage in ketamine-naive patients is 0.5 mg/kg racemic ketamine or 0.25 mg/kg S-ketamine as a single oral dose. The dosage is increased by the same amount if required. For a continuous analgesic effect it is usually given 3-4 times daily. The injection fluid can be taken orally. When parenteral ketamine is switched to oral administration the daily dosage can be kept equal and, depending on clinical effect and/or adverse effects, is slowly increased. The pharmacologically active metabolite norketamine is believed to contribute to the analgesic effect of oral ketamine. Lack of evidence regarding efficacy, and the poor safety profile, do not support routine use of oral ketamine in chronic pain management. Oral ketamine may have a limited place as add-on therapy in complex chronic pain patients if other therapeutic options have failed. (C) 2009 European Federation of International Association for the Study of Pain Chapters. Published by Elsevier Ltd. All rights reserved

The efficacy, pharmacokinetics, and safety of a nevirapine to rilpivirine switch in virologically suppressed HIV-1-infected patients

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Pharmacokinetic Drug-Drug Interaction Study Between Raltegravir and Atorvastatin 20 mg in Healthy Volunteers

Contains fulltext : 153639.pdf (publisher's version ) (Closed access)BACKGROUND: Dyslipidemia is highly prevalent among patients with HIV infection and contributes to an increased risk of cardiovascular disease. We investigated the influence of a frequently used statin, atorvastatin, on the pharmacokinetics of the HIV-integrase inhibitor raltegravir and vice versa. METHODS: Open-label, crossover 3-period phase I trial in 24 healthy volunteers. Subjects took raltegravir 400 mg two times a day for 7 days, atorvastatin 20 mg once a day for 7 days, and the combination of atorvastatin 20 mg once a day + raltegravir 400 mg two times a day for 7 days with 2-week washout periods in between. Intensive steady-state 12- and 24-hour pharmacokinetic blood sampling was performed. Geometric mean ratios of the test treatment (combination raltegravir + atorvastatin) versus the reference treatment (raltegravir or atorvastatin alone) and 90% confidence intervals were calculated for the area under the plasma concentration-time curve (AUC). Fasting lipid profiles were obtained to assess short-term lipid-lowering effect of atorvastatin with or without concomitant raltegravir use. RESULTS: Twenty-four healthy volunteers (11 males) were enrolled. All but 1 subject completed the trial, and no serious adverse events were reported. Geometric mean ratios (90% confidence interval) were 1.01 (0.68-1.51) for raltegravir AUC0-12h and 1.00 (0.90-1.11) for atorvastatin AUC0-24h. The AUC0-24h metabolite-to-parent ratio for atorvastatin lactone, ortho-hydroxy, and para-hydroxy atorvastatin did not change during concomitant raltegravir use. The effect of atorvastatin on low-density lipoprotein cholesterol was not significantly different when combined with raltegravir versus atorvastatin alone (P = 0.638). CONCLUSIONS: Atorvastatin 20 mg has no clinically relevant effect on the pharmacokinetics of raltegravir and vice versa. The combination was well tolerated and can be administered without dose adjustments

Pharmacokinetic drug-drug interaction study between raltegravir and citalopram

BACKGROUND: Depression is the most common mental health disorder among HIV-infected patients. When treating HIV-infected patients with a selective serotonin reuptake inhibitor (SSRI), potential drug-drug interactions with antiretroviral agents have to be taken into account. We investigated the two-way pharmacokinetic drug-drug interaction and tolerability of concomitant administration of the SSRI citalopram and the HIV-1 integrase inhibitor raltegravir in healthy volunteers. METHODS: An open-label, crossover, two-period trial was conducted in 24 healthy volunteers. Subjects received the following treatments: citalopram 20 mg once daily for 2 weeks followed by the combination with raltegravir 400 mg twice daily for 5 days and after a washout period raltegravir 400 mg twice daily for 5 days. Intensive steady-state pharmacokinetic blood sampling was performed. Geometric mean ratios (GMRs) of the combination versus the reference treatment and 90% CIs were calculated for the area under the plasma concentration-time curve (AUC). CYP2C19 genotyping was performed because it influences N-demethylation of citalopram to desmethylcitalopram. RESULTS: A total of 22 healthy volunteers completed the trial. GMRs (90% CI) were 1.00 (0.98, 1.03) for citalopram AUC0-24 h, 0.99 (0.88, 1.12) for desmethylcitalopram AUC0-24 h and 0.77 (0.50, 1.19) for raltegravir AUC0-12 h. Raltegravir plasma concentration 12 h after intake (C12 h) did not change with concomitant use of citalopram. Within each CYP2C19 phenotype subgroup the citalopram metabolite-to-parent ratio, which is a measure for metabolic enzyme activity, was not influenced by concomitant raltegravir use. CONCLUSIONS: Raltegravir does not influence the pharmacokinetics of citalopram and desmethylcitalopram. Citalopram did not change the pharmacokinetics of raltegravir in a clinically meaningful way. The combination was well tolerated and can be administered without dose adjustments. ClinicalTrials.gov NCT01978782

CYP2D6*4, CYP3A5*3 and ABCB1 3435T polymorphisms and drug-related falls in elderly people

The objective of this study is to investigate the association between CYP2D6*4, CYP3A5*3 and ABCB1 3435T polymorphisms and drug-related falls. Multivariate logistic regression was performed in an existing database in order to study the association between falls history and CYP2D6*4, CYP3A5*3, ABCB1 3435T polymorphisms in patients using fall-risk-increasing CYP2D6, CYP3A5 and P-glycoprotein (gene product of ABCB1) substrates. No statistically significant increased fall risk was found in 'poor metabolizers' compared to 'extensive' and 'intermediate metabolizers' using fall-risk-increasing CYP2D6 substrates (Odds ratio (OR) = 2.2; 95% confidence interval (CI) 0.2-25.0), CYP3A5 substrates (OR = 0.9; 95% CI 0.2-3.3) and P-glycoprotein substrates (OR = 2.1; 95% CI 0.2-17.2). The hypothesis that 'poor metabolizers' have an increased fall risk was not confirmed. A larger study population is needed to confirm the potential association that was seen between CYP2D6*4 and ABCB1 3435T polymorphisms and drug-related fall

Raltegravir in HIV-1-Infected Pregnant Women: Pharmacokinetics, Safety, and Efficacy

Contains fulltext : 153803.pdf (publisher's version ) (Closed access)BACKGROUND: The use of raltegravir in human immunodeficiency virus (HIV)-infected pregnant women is important in the prevention of mother-to-child HIV transmission, especially in circumstances when a rapid decline of HIV RNA load is warranted or when preferred antiretroviral agents cannot be used. Physiological changes during pregnancy can reduce antiretroviral drug exposure. We studied the effect of pregnancy on the pharmacokinetics of raltegravir and its safety and efficacy in HIV-infected pregnant women. METHODS: An open-label, multicenter, phase 4 study in HIV-infected pregnant women receiving raltegravir 400 mg twice daily was performed (Pharmacokinetics of Newly Developed Antiretroviral Agents in HIV-Infected Pregnant Women Network). Steady-state pharmacokinetic profiles were obtained in the third trimester and postpartum along with cord and maternal delivery concentrations. Safety and virologic efficacy were evaluated. RESULTS: Twenty-two patients were included, of which 68% started raltegravir during pregnancy. Approaching delivery, 86% of the patients had an undetectable viral load (<50 copies/mL). None of the children were HIV-infected. Exposure to raltegravir was highly variable. Overall area under the plasma concentration-time curve (AUC) and plasma concentration at 12 hours after intake (C12h) plasma concentrations in the third trimester were on average 29% and 36% lower, respectively, compared with postpartum: Geometric mean ratios (90% confidence interval) were 0.71 (.53-.96) for AUC0-12h and 0.64 (.34-1.22) for C12h. The median ratio of raltegravir cord to maternal blood was 1.21 (interquartile range, 1.02-2.17; n = 9). CONCLUSIONS: Raltegravir was well tolerated during pregnancy. The pharmacokinetics of raltegravir showed extensive variability. The observed mean decrease in exposure to raltegravir during third trimester compared to postpartum is not considered to be of clinical importance. Raltegravir can be used in standard dosages in HIV-infected pregnant women. CLINICAL TRIALS REGISTRATION: NCT00825929