RÉSUMÉ
Ripretinib is a switch control KIT kinase inhibitor approved for treatment of adults with advanced gastrointestinal stromal tumors who received prior treatment with 3 or more kinase inhibitors, including imatinib. Ripretinib and its active metabolite (DP-5439) are cleared mainly via cytochrome P450 enzyme 3A4/5 (CYP3A4/5), and ripretinib solubility is pH-dependent, thus the drug-drug interaction potentials of ripretinib with itraconazole (strong CYP3A inhibitor), rifampin (strong CYP3A inducer), and pantoprazole (proton pump inhibitor) were each evaluated in open-label, fixed-sequence study designs. Overall, 20 participants received ripretinib 50 mg alone and with itraconazole 200 mg once daily, 24 participants received ripretinib 100 mg alone and with rifampin 600 mg once daily, and 25 participants received ripretinib 50 mg alone and with pantoprazole 40 mg once daily. Ripretinib exposure increased with concomitant itraconazole, with geometric least-squares (LS) mean ratios of ripretinib area under the concentration-time curve from 0 to ∞ (AUC0-∞ ) and maximum observed concentration (Cmax ) of 199% and 136%. Ripretinib exposure decreased with concomitant rifampin: geometric LS mean ratios for ripretinib AUC0-∞ and Cmax were 39% and 82%. Pantoprazole coadministration had no effect on ripretinib pharmacokinetics. No unexpected safety signals occurred. No dose adjustment is required for ripretinib coadministered with gastric acid reducers and strong CYP3A inhibitors; patients also receiving strong CYP3A inhibitors should be monitored more frequently for adverse reactions. Concomitant ripretinib use with strong CYP3A inducers should be avoided. Prescribers should refer to approved labeling for specific dose recommendations with concomitant use of strong and moderate CYP3A inducers.
Sujet(s)
Inducteurs du cytochrome P-450 CYP3A , Inhibiteurs du cytochrome P-450 CYP3A , Inhibiteurs de protéines kinases , Adulte , Association de médicaments/effets indésirables , Acide gastrique/métabolisme , Humains , Mésilate d'imatinib , Itraconazole/pharmacologie , Naphtyridines/pharmacocinétique , Pantoprazole , Inhibiteurs de protéines kinases/pharmacocinétique , Inhibiteurs de la pompe à protons , Rifampicine , Urée/analogues et dérivésRÉSUMÉ
Model-informed drug development (MIDD) has a long and rich history in infectious diseases. This review describes foundational principles of translational anti-infective pharmacology, including choice of appropriate measures of exposure and pharmacodynamic (PD) measures, patient subpopulations, and drug-drug interactions. Examples are presented for state-of-the-art, empiric, mechanistic, interdisciplinary, and real-world evidence MIDD applications in the development of antibacterials (review of minimum inhibitory concentration-based models, mechanism-based pharmacokinetic/PD (PK/PD) models, PK/PD models of resistance, and immune response), antifungals, antivirals, drugs for the treatment of global health infectious diseases, and medical countermeasures. The degree of adoption of MIDD practices across the infectious diseases field is also summarized. The future application of MIDD in infectious diseases will progress along two planes; "depth" and "breadth" of MIDD methods. "MIDD depth" refers to deeper incorporation of the specific pathogen biology and intrinsic and acquired-resistance mechanisms; host factors, such as immunologic response and infection site, to enable deeper interrogation of pharmacological impact on pathogen clearance; clinical outcome and emergence of resistance from a pathogen; and patient and population perspective. In particular, improved early assessment of the emergence of resistance potential will become a greater focus in MIDD, as this is poorly mitigated by current development approaches. "MIDD breadth" refers to greater adoption of model-centered approaches to anti-infective development. Specifically, this means how various MIDD approaches and translational tools can be integrated or connected in a systematic way that supports decision making by key stakeholders (sponsors, regulators, and payers) across the entire development pathway.
Sujet(s)
Anti-infectieux/pharmacologie , Développement de médicament/organisation et administration , Modèles biologiques , Food and Drug Administration (USA)/organisation et administration , Antibactériens/pharmacologie , Anti-infectieux/pharmacocinétique , Antifongiques/pharmacologie , Antipaludiques/pharmacologie , Antituberculeux/pharmacologie , Antiviraux/pharmacologie , Poids , Relation dose-effet des médicaments , Agrément de médicaments/organisation et administration , Découverte de médicament/organisation et administration , Résistance microbienne aux médicaments/effets des médicaments et des substances chimiques , Résistance microbienne aux médicaments/physiologie , Humains , Immunité/physiologie , Ivermectine/usage thérapeutique , Tests de la fonction rénale , Tests de la fonction hépatique , Tests de sensibilité microbienne , Onchocercose oculaire/traitement médicamenteux , Pédiatrie , Plan de recherche , États-Unis , Food and Drug Administration (USA)/normesRÉSUMÉ
BACKGROUND: Neonatal enterovirus sepsis has high mortality. Antiviral therapy is not available. METHODS: Neonates with suspected enterovirus sepsis (hepatitis, coagulopathy, and/or myocarditis) with onset at ≤15 days of life were randomized 2:1 to receive oral pleconaril or placebo for 7 days. Serial virologic (oropharynx, rectum, urine, serum), clinical, pharmacokinetic, and safety evaluations were performed. RESULTS: Sixty-one subjects were enrolled (43 treatment, 18 placebo), of whom 43 were confirmed enterovirus infected (31 treatment, 12 placebo). There was no difference in day 5 oropharyngeal culture positivity (primary endpoint; 0% in both groups). However, enterovirus-infected subjects in the treatment group became culture negative from all anatomic sites combined faster than placebo group subjects (median 4.0 versus 7.0 days, P = .08), and fewer subjects in the treatment group remained polymerase chain reaction (PCR)-positive from the oropharynx when last sampled (23% versus 58%, P = .02; median, 14.0 days). By intent to treat, 10/43 (23%) subjects in the treatment group and 8/18 (44%) in the placebo group died (P = .02 for 2-month survival difference); among enterovirus-confirmed subjects, 7/31 (23%) in the treatment group died versus 5/12 (42%) in the placebo group (P = .26). All pleconaril recipients attained concentrations greater than the IC90 after the first study day, but 38% were less than the IC90 during the first day of treatment. One subject in the treatment group and three in the placebo group had treatment-related adverse events. CONCLUSIONS: Shorter times to culture and PCR negativity and greater survival among pleconaril recipients support potential efficacy and warrant further evaluation.
Sujet(s)
Antiviraux/usage thérapeutique , Infections à entérovirus/complications , Infections à entérovirus/traitement médicamenteux , Enterovirus/effets des médicaments et des substances chimiques , Sepsis néonatal/traitement médicamenteux , Sepsis néonatal/virologie , Oxadiazoles/usage thérapeutique , Antiviraux/sang , Antiviraux/pharmacocinétique , Antiviraux/urine , Méthode en double aveugle , Enterovirus/génétique , Enterovirus/isolement et purification , Infections à entérovirus/sang , Infections à entérovirus/urine , Femelle , Humains , Nourrisson , Nouveau-né , Mâle , Sepsis néonatal/sang , Sepsis néonatal/urine , Partie orale du pharynx/virologie , Oxadiazoles/sang , Oxadiazoles/pharmacocinétique , Oxadiazoles/urine , Oxazoles , Rectum/virologieRÉSUMÉ
INTRODUCTION: New treatment options are needed for second-line therapy in patients with NSCLC. PATIENTS AND METHODS: This was a phase Ib/II study in patients with nonsquamous NSCLC in whom 1 previous platinum-based chemotherapy regimen had failed. Fifteen patients were enrolled in a dose escalation of eribulin mesylate in combination with pemetrexed (E+P). In phase II (n = 80), E+P at the maximum tolerated dose was compared with P. RESULTS: In phase Ib, the maximum tolerated dose of E+P was defined as eribulin 0.9 mg/m(2) with pemetrexed (500 mg/m(2)) each on day 1 of a 21-day cycle. In phase II, adverse events were comparable between groups. PFS and OS were similar between treatment groups. Median PFS was 21.4 weeks for E+P (n = 26; 95% confidence interval [CI], 12.7-39.6) and 23.4 weeks for P (n = 29; 95% CI, 17.1-29.9), with a hazard ratio of 1.0 (95% CI, 0.6-1.7). CONCLUSION: During phase Ib, E+P was tolerated only at a markedly lower dosing intensity relative to the eribulin monotherapy regimen approved for breast cancer and used in phase II studies of NSCLC. At the selected phase II dosing regimen, E+P was generally safe and well tolerated but provided no therapeutic advantage for the second-line treatment of locally advanced or metastatic nonsquamous NSCLC.
Sujet(s)
Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , Carcinome pulmonaire non à petites cellules/traitement médicamenteux , Tumeurs du poumon/traitement médicamenteux , Adulte , Sujet âgé , Sujet âgé de 80 ans ou plus , Antimétabolites antinéoplasiques/administration et posologie , Antimétabolites antinéoplasiques/effets indésirables , Antimétabolites antinéoplasiques/usage thérapeutique , Protocoles de polychimiothérapie antinéoplasique/administration et posologie , Protocoles de polychimiothérapie antinéoplasique/effets indésirables , Carcinome pulmonaire non à petites cellules/anatomopathologie , Survie sans rechute , Relation dose-effet des médicaments , Femelle , Furanes/administration et posologie , Glutamates/administration et posologie , Guanine/administration et posologie , Guanine/analogues et dérivés , Humains , Cétones/administration et posologie , Tumeurs du poumon/anatomopathologie , Mâle , Dose maximale tolérée , Adulte d'âge moyen , Pémétrexed , Taux de survie , Résultat thérapeutiqueRÉSUMÉ
BACKGROUND: Poor neurodevelopmental outcomes and recurrences of cutaneous lesions remain unacceptably frequent among survivors of neonatal herpes simplex virus (HSV) disease. METHODS: We enrolled neonates with HSV disease in two parallel, identical, double-blind, placebo-controlled studies. Neonates with central nervous system (CNS) involvement were enrolled in one study, and neonates with skin, eye, and mouth involvement only were enrolled in the other. After completing a regimen of 14 to 21 days of parenteral acyclovir, the infants were randomly assigned to immediate acyclovir suppression (300 mg per square meter of body-surface area per dose orally, three times daily for 6 months) or placebo. Cutaneous recurrences were treated with open-label episodic therapy. RESULTS: A total of 74 neonates were enrolled--45 with CNS involvement and 29 with skin, eye, and mouth disease. The Mental Development Index of the Bayley Scales of Infant Development (in which scores range from 50 to 150, with a mean of 100 and with higher scores indicating better neurodevelopmental outcomes) was assessed in 28 of the 45 infants with CNS involvement (62%) at 12 months of age. After adjustment for covariates, infants with CNS involvement who had been randomly assigned to acyclovir suppression had significantly higher mean Bayley mental-development scores at 12 months than did infants randomly assigned to placebo (88.24 vs. 68.12, P=0.046). Overall, there was a trend toward more neutropenia in the acyclovir group than in the placebo group (P=0.09). CONCLUSIONS: Infants surviving neonatal HSV disease with CNS involvement had improved neurodevelopmental outcomes when they received suppressive therapy with oral acyclovir for 6 months. (Funded by the National Institute of Allergy and Infectious Diseases; CASG 103 and CASG 104 ClinicalTrials.gov numbers, NCT00031460 and NCT00031447, respectively.).
Sujet(s)
Aciclovir/usage thérapeutique , Antiviraux/usage thérapeutique , Maladies du système nerveux central/traitement médicamenteux , Développement de l'enfant/effets des médicaments et des substances chimiques , Herpès/traitement médicamenteux , Complications infectieuses de la grossesse/traitement médicamenteux , Aciclovir/effets indésirables , Antiviraux/effets indésirables , Maladies du système nerveux central/prévention et contrôle , Maladies du système nerveux central/virologie , Méthode en double aveugle , Femelle , Herpès/prévention et contrôle , Humains , Nouveau-né , Estimation de Kaplan-Meier , Mâle , Prévention secondaireRÉSUMÉ
Zanamivir serum and pulmonary pharmacokinetics were characterized following intravenous (i.v.) or oral inhaled administration. I.v. zanamivir was given as intermittent doses of 100 mg, 200 mg, and 600 mg every 12 h (q12h) for two doses or as a continuous infusion (6-mg loading dose followed by 3 mg/h for 12 h). Oral inhaled zanamivir (two 5-mg inhalations q12h for two doses) was evaluated as well. Each zanamivir regimen was administered to six healthy subjects with serial pharmacokinetic sampling. In addition, a single bronchoalveolar lavage (BAL) fluid sample was collected at various time points and used to calculate epithelial lining fluid (ELF) drug concentrations for each subject. For intermittent i.v. administration of 100 mg, 200 mg, and 600 mg zanamivir, the median zanamivir concentrations in ELF collected 12 h after dosing were 74, 146, and 419 ng/ml, respectively, each higher than the historic mean 50% inhibitory concentrations for the neuraminidases of wild-type strains of influenza A and B viruses. Median ELF/serum zanamivir concentration ratios ranged from 55 to 79% for intermittent i.v. administration (when sampled 12 h after the last dose) and 43 to 45% for continuous infusion (when sampled 6 to 12 h after the start of the infusion). For oral inhaled zanamivir, the median zanamivir concentrations in ELF were 891 ng/ml for the first BAL fluid collection and 326 ng/ml for subsequent BAL fluid collections (when sampled 12 h after the last dose); corresponding serum drug concentrations were undetectable. This study demonstrates zanamivir's penetration into the human pulmonary compartment and supports the doses selected for the continuing development of i.v. zanamivir in clinical studies of influenza.
Sujet(s)
Poumon/métabolisme , Zanamivir/administration et posologie , Zanamivir/pharmacocinétique , Administration par inhalation , Administration par voie orale , Adolescent , Adulte , Liquide de lavage bronchoalvéolaire/composition chimique , Humains , Mâle , Adulte d'âge moyen , Jeune adulteRÉSUMÉ
BACKGROUND & AIMS: Pegylated interferon (PEG-IFN) alfa-2b plus ribavirin (RBV) is the standard of care for adults with chronic hepatitis C but was not approved for the treatment of children at the time of this study. The aim of this study was to evaluate the efficacy and safety of PEG-IFN alfa-2b plus RBV in children. METHODS: Children and adolescents ages 3-17 years were treated with PEG-IFN alfa-2b (60microg/m(2)/week) plus RBV (15mg/kg/day). The duration of therapy was 24 weeks for genotype (G) 2 and G3 patients with low viral load (<600,000IU/ml) and 48 weeks for G1, G4, and G3 with high viral load (>or=600,000IU/ml). The primary end point was sustained virologic response (SVR), defined as undetectable hepatitis C virus (HCV) RNA 24 weeks after completion of therapy. RESULTS: SVR was attained by 70 (65%) children. Genotype was the main predictor of response: G1, 53%; G2/3, 93%; G4, 80%. SVRs were similar in younger and older children. Baseline viral load was the main predictor of response in the G1 cohort. No new safety signals were identified, and adverse events (AEs) were generally mild or moderate in severity. Dose was modified because of AEs in 25% of children; 1 child discontinued because of an AE (thrombocytopenia). No serious AEs related to study drugs were reported. CONCLUSION: Therapy with PEG-IFN alfa-2b plus RBV in children and adolescents with chronic hepatitis C offers favorable efficacy, reduced injection frequency, and an acceptable safety profile.
Sujet(s)
Antiviraux/administration et posologie , Hepacivirus/effets des médicaments et des substances chimiques , Hépatite C chronique/traitement médicamenteux , Interféron alpha/administration et posologie , Polyéthylène glycols/administration et posologie , Ribavirine/administration et posologie , Adolescent , Antiviraux/effets indésirables , Antiviraux/pharmacocinétique , Taille , Poids , Enfant , Développement de l'enfant , Enfant d'âge préscolaire , Résistance virale aux médicaments/génétique , Association de médicaments , Femelle , Génotype , Hepacivirus/génétique , Hépatite C chronique/virologie , Humains , Interféron alpha-2 , Interféron alpha/effets indésirables , Interféron alpha/pharmacocinétique , Mâle , Polyéthylène glycols/effets indésirables , Polyéthylène glycols/pharmacocinétique , Protéines recombinantes , Ribavirine/effets indésirables , Ribavirine/pharmacocinétique , Résultat thérapeutique , Charge virale/effets des médicaments et des substances chimiquesRÉSUMÉ
BACKGROUND: When oseltamivir is administered in extremely high doses (500-1000 mg/kg) to young juvenile rats, central nervous system toxicity and death occurred in some animals. Mortality was not observed in older juvenile rats, suggesting a possible relationship between neurotoxicity and an immature blood-brain barrier. To assess potential neurologic adverse effects of oseltamivir use in infants, a retrospective chart review was performed in infants less than 12 months of age who received oseltamivir, amantadine, or rimantadine. METHODS: The primary objective was to describe the frequency of neurologic adverse events among children less than 12 months of age who received oseltamivir compared with those receiving adamantanes. Medical record databases, emergency department databases, and/or pharmacy records at 15 medical centers were searched to identify patients. RESULTS: Of the 180 infants identified as having received antiviral therapy, 115 (64%) received oseltamivir, 37 (20%) received amantadine, and 28 (16%) received rimantadine. The median dose of oseltamivir was 2.0 mg/kg/dose in 3- to 5-month-old and 2.2 mg/kg/dose in 9- to 12-month-old infants. The maximum dose administered was 7.0 mg/kg/dose. There were no statistically significant differences in the occurrence of adverse neurologic events during therapy among subjects treated with oseltamivir versus those treated with the adamantanes (P = 0.13). CONCLUSIONS: This is the largest report to date of oseltamivir use in children less than 12 months of age. Neurologic events were not more common with use of oseltamivir compared with that of the adamantanes. Dosing of oseltamivir was variable, illustrating the need for pharmacokinetic data in this younger population.
Sujet(s)
Adamantane/effets indésirables , Antiviraux/effets indésirables , Grippe humaine/traitement médicamenteux , Oséltamivir/effets indésirables , Rimantadine/effets indésirables , Adamantane/usage thérapeutique , Antiviraux/usage thérapeutique , Système nerveux central/effets des médicaments et des substances chimiques , Femelle , Humains , Nourrisson , Nouveau-né , Mâle , Maladies du système nerveux/induit chimiquement , Oséltamivir/usage thérapeutique , Études rétrospectives , Rimantadine/usage thérapeutiqueRÉSUMÉ
BACKGROUND: Ganciclovir protects against hearing deterioration in infants with symptomatic congenital cytomegalovirus (CMV) disease involving the central nervous system (CNS). OBJECTIVES: To assess the neurodevelopmental impact of ganciclovir therapy in this population. STUDY DESIGN: 100 neonates were enrolled into a controlled Phase III study of symptomatic congenital CMV involving the CNS, and were randomized to either 6 weeks of intravenous ganciclovir or no treatment. Denver developmental tests were performed at 6 weeks, 6 months, and 12 months. For each age, developmental milestones that > or =90% of normal children would be expected to have achieved were identified. The numbers of milestones not met ("delays") were determined for each subject. The average number of delays per subject was compared for each treatment group. RESULTS: At 6 months, the average number of delays was 4.46 and 7.51, respectively, for ganciclovir recipients and "no treatment" subjects (p=0.02). At 12 months, the average number of delays was 10.06 and 17.14, respectively (p=0.007). In a multivariate regression model, the effect of ganciclovir therapy remained statistically significant at 12 months (p=0.007). CONCLUSIONS: Infants with symptomatic congenital CMV involving the CNS receiving intravenous ganciclovir therapy have fewer developmental delays at 6 and 12 months compared with untreated infants. Based on these data as well as the previously published data regarding ganciclovir treatment and hearing outcomes, 6 weeks of intravenous ganciclovir therapy can be considered in the management of babies with symptomatic congenital CMV disease involving the CNS. If treatment is initiated, it should be started within the first month of life and patients should be monitored closely for toxicity, especially neutropenia. Since existing data only address the treatment of symptomatic congenital CMV disease involving the CNS, these data cannot be extrapolated to neonates with other manifestations of CMV disease, including asymptomatic babies and symptomatic babies who do not have CNS involvement.
Sujet(s)
Antiviraux/usage thérapeutique , Système nerveux central/virologie , Infections à cytomégalovirus/traitement médicamenteux , Incapacités de développement/prévention et contrôle , Ganciclovir/usage thérapeutique , Antiviraux/administration et posologie , Système nerveux central/physiopathologie , Infections à cytomégalovirus/complications , Infections à cytomégalovirus/congénital , Incapacités de développement/virologie , Femelle , Ganciclovir/administration et posologie , Humains , Nourrisson , Nouveau-né , Injections veineuses , Mâle , Analyse multifactorielle , Analyse de régression , Résultat thérapeutiqueRÉSUMÉ
Rifabutin (RFB) is administered for treatment of tuberculosis and Mycobacterium avium complex infection, including use for patients coinfected with human immunodeficiency virus (HIV). Increased systemic exposure to RFB and its equipotent active metabolite, 25-O-desacetyl-RFB (dAc-RFB), has been reported during concomitant administration of CYP3A4 inhibitors, including ritonavir (RTV), lopinavir, and amprenavir (APV); therefore, a reduction in the RFB dosage is recommended when it is coadministered with these protease inhibitors. Fosamprenavir (FPV), the phosphate ester prodrug of the HIV type 1 protease inhibitor APV, is administered either with or without RTV. A randomized, open-label, two-period, two-sequence, balanced, crossover drug interaction study was conducted with 22 healthy adult subjects to compare steady-state plasma RFB pharmacokinetic parameters during concomitant administration of FPV-RTV (700/100 mg twice a day [BID]) with a 75%-reduced RFB dose (150 mg every other day [QOD]) to the standard RFB regimen (300 mg once per day [QD]) by geometric least-squares mean ratios. Relative to results with RFB (300 mg QD), coadministration of dose-adjusted RFB with FPV-RTV resulted in an unchanged RFB area under the concentration-time curve for 0 to 48 h (AUC(0-48)) and a 14% decrease in the maximum concentration of drug in plasma (C(max)), whereas the AUC(0-48) and C(max) of dAc-RFB were increased by 11- and 6-fold, respectively, resulting in a 64% increase in the total antimycobacterial AUC(0-48). Relative to historical controls, the plasma APV AUC from 0 h to the end of the dosing interval (AUC(0-tau)) and C(max) were increased approximately 35%, and the concentration at the end of the dosing interval at steady state was unchanged following coadministration of RFB with FPV-RTV. The safety profile of the combination of RFB and FPV-RTV was consistent with previously described events with RFB or FPV-RTV alone. Based on the results of this study, a reduction in the RFB dose by > or =75% (to 150 mg QOD or three times per week) is recommended when it is coadministered with FPV-RTV (700/100 mg BID).
Sujet(s)
Antituberculeux/pharmacocinétique , Carbamates/pharmacocinétique , Organophosphates/pharmacocinétique , Rifabutine/pharmacocinétique , Ritonavir/pharmacocinétique , Sulfonamides/pharmacocinétique , Adulte , Antituberculeux/effets indésirables , Antituberculeux/sang , Aire sous la courbe , Carbamates/effets indésirables , Carbamates/sang , Études croisées , Calendrier d'administration des médicaments , Interactions médicamenteuses , Association de médicaments , Femelle , Furanes , Humains , Mâle , Adulte d'âge moyen , Organophosphates/effets indésirables , Organophosphates/sang , Rifabutine/effets indésirables , Rifabutine/sang , Ritonavir/effets indésirables , Ritonavir/sang , Sulfonamides/effets indésirables , Sulfonamides/sangRÉSUMÉ
Plasma ketoconazole (KETO), amprenavir (APV), and ritonavir (RTV) pharmacokinetics were evaluated in 15 healthy subjects after being treated with KETO at 200 mg once daily (QD), fosamprenavir (FPV)/RTV at 700/100 mg twice daily (BID), and then KETO at 200 mg QD plus FPV/RTV at 700/100 mg BID in this open-label study. The KETO area under the concentration-time curve at steady state was increased 2.69-fold with FPV/RTV. APV exposure was unchanged, and RTV exposure was slightly increased.
Sujet(s)
Antifongiques/pharmacocinétique , Carbamates/pharmacocinétique , Inhibiteurs de protéase du VIH/pharmacocinétique , Kétoconazole/pharmacocinétique , Ritonavir/pharmacocinétique , Sulfonamides/pharmacocinétique , Adolescent , Adulte , Antifongiques/administration et posologie , Antifongiques/sang , Aire sous la courbe , Carbamates/administration et posologie , Carbamates/sang , Interactions médicamenteuses , Association de médicaments , Femelle , Furanes , Inhibiteurs de protéase du VIH/administration et posologie , Inhibiteurs de protéase du VIH/sang , Humains , Kétoconazole/administration et posologie , Kétoconazole/sang , Mâle , Adulte d'âge moyen , Organophosphates/administration et posologie , Organophosphates/sang , Organophosphates/pharmacocinétique , Ritonavir/administration et posologie , Ritonavir/sang , Sulfonamides/administration et posologie , Sulfonamides/sang , Résultat thérapeutiqueRÉSUMÉ
Once-daily (QD) fosamprenavir (FPV) at 1,400 mg boosted with low-dose ritonavir (RTV) at 200 mg is effective when it is used in combination regimens for the initial treatment of human immunodeficiency virus infection. Whether a lower RTV boosting dose (i.e., 100 mg QD) could ensure sufficient amprenavir (APV) concentrations with improved safety/tolerability is unknown. This randomized, two 14-day-period, crossover pharmacokinetic study compared the steady-state plasma APV concentrations, safety, and tolerability of FPV at 1,400 mg QD boosted with either 100 mg or 200 mg of RTV QD in 36 healthy volunteers. Geometric least-square (GLS) mean ratios and the associated 90% confidence intervals (CIs) were estimated for plasma APV maximum plasma concentrations (Cmax), the area under the plasma concentration-time curve over the dosing period (AUC0-tau), and trough concentrations (Ctau) during each dosing period. Equivalence between regimens (90% CIs of GLS mean ratios, 0.80 to 1.25) was observed for the plasma APV AUC0-tau (GLS mean ratio, 0.90 [90% CI, 0.84 to 0.96]) and Cmax (0.97 [90% CI, 0.91 to 1.04]). The APV Ctau was 38% lower with RTV at 100 mg QD than with RTV at 200 mg QD (GLS mean ratio, 0.62 [90% CI, 0.55 to 0.69]) but remained sixfold higher than the protein-corrected 50% inhibitory concentration for wild-type virus, with the lowest APV Ctau observed during the 100-mg QD period being nearly threefold higher. The GLS mean APV Ctau was 2.5 times higher than the historical Ctau for unboosted FPV at 1,400 mg twice daily. Fewer clinical adverse drug events and smaller increases in triglyceride levels were observed with the RTV 100-mg QD regimen. Clinical trials evaluating the efficacy and safety of FPV at 1,400 mg QD boosted by RTV at 100 mg QD are now under way with antiretroviral therapy-naïve patients.
Sujet(s)
Agents antiVIH/pharmacocinétique , Carbamates/pharmacocinétique , Organophosphates/pharmacocinétique , Ritonavir/pharmacocinétique , Sulfonamides/pharmacocinétique , Adolescent , Adulte , Agents antiVIH/administration et posologie , Agents antiVIH/effets indésirables , Agents antiVIH/sang , Thérapie antirétrovirale hautement active , Carbamates/administration et posologie , Carbamates/effets indésirables , Carbamates/sang , Femelle , Furanes , Infections à VIH/sang , Infections à VIH/traitement médicamenteux , Humains , Mâle , Adulte d'âge moyen , Organophosphates/administration et posologie , Organophosphates/effets indésirables , Promédicaments/administration et posologie , Promédicaments/effets indésirables , Promédicaments/pharmacocinétique , Ritonavir/administration et posologie , Ritonavir/effets indésirables , Sulfonamides/administration et posologie , Sulfonamides/effets indésirables , Sulfonamides/sangRÉSUMÉ
Fosamprenavir (FPV) with and without ritonavir (RTV) was added to the antiretroviral regimens of human immunodeficiency virus-infected subjects receiving nevirapine (NVP) to evaluate this drug interaction. Significant reductions in plasma amprenavir exposure (25 to 35%) were observed following coadministration of 1,400 mg of FPV twice a day (BID) and 200 mg of NVP BID. A regimen of 700 mg of FPV BID plus 100 mg of RTV BID may be coadministered with NVP without dose adjustment.
Sujet(s)
Agents antiVIH/pharmacologie , Carbamates/pharmacologie , Infections à VIH/traitement médicamenteux , VIH (Virus de l'Immunodéficience Humaine) , Névirapine/pharmacologie , Organophosphates/pharmacologie , Ritonavir/pharmacologie , Sulfonamides/pharmacologie , Adulte , Interactions médicamenteuses , Femelle , Furanes , Inhibiteurs de protéase du VIH/pharmacologie , Humains , Mâle , Inhibiteurs de la transcriptase inverse/pharmacologieRÉSUMÉ
OBJECTIVES: To evaluate the drug interaction between fosamprenavir (FPV) and esomeprazole (ESO) after repeated doses in healthy adults. METHODS: Subjects received ESO 20 mg once daily (qd) for 7 days followed by either ESO 20 mg qd + FPV 1400 mg twice daily (bid) or ESO 20 mg qd + FPV 700 mg bid + ritonavir (RTV) 100 mg bid for 14 days in arms 1 and 2, respectively. After a 21- to 28-day washout, subjects received either FPV 1400 mg bid for 14 days (arm 1) or FPV 700 mg bid + RTV 100 mg bid for 14 days (arm 2). Pharmacokinetic sampling was conducted on the last day of each treatment. RESULTS: Simultaneous coadministration of ESO 20 mg qd with either FPV 1400 mg bid or FPV 700 mg bid + RTV 100 mg bid had no effect on steady-state amprenavir pharmacokinetics. The only effect on plasma ESO exposure was a 55% increase in area under the plasma concentration-time curve during a dosing interval, tau[AUC0-tau], after coadministration of ESO 20 mg qd with FPV 1400 mg bid. CONCLUSIONS: FPV 1400 mg bid or FPV 700 mg bid + RTV 100 mg bid may be coadministered simultaneously with ESO without dose adjustment. However, the impact of staggered administration of proton pump inhibitors (PPI) on plasma amprenavir exposure is unknown at present.
Sujet(s)
Carbamates/administration et posologie , Carbamates/pharmacocinétique , Ésoméprazole/administration et posologie , Organophosphates/administration et posologie , Sulfonamides/administration et posologie , Sulfonamides/pharmacocinétique , Administration par voie orale , Adolescent , Adulte , Carbamates/effets indésirables , Carbamates/sang , Diarrhée/induit chimiquement , Calendrier d'administration des médicaments , Association médicamenteuse , Ésoméprazole/effets indésirables , Femelle , Furanes , Céphalée/induit chimiquement , Humains , Mâle , Adulte d'âge moyen , Nausée/induit chimiquement , Organophosphates/effets indésirables , Ritonavir/administration et posologie , Ritonavir/effets indésirables , Sulfonamides/effets indésirables , Sulfonamides/sangRÉSUMÉ
To compare the effect of ritonavir on plasma amprenavir pharmacokinetics, healthy adults received either fosamprenavir (700 mg twice a day [BID]) or amprenavir (600 mg BID) alone and in combination with ritonavir (100 mg BID). Ritonavir increased plasma amprenavir pharmacokinetic parameters to a similar extent when coadministered with either fosamprenavir or amprenavir.
Sujet(s)
Carbamates/pharmacologie , Inhibiteurs de protéase du VIH/pharmacologie , Organophosphates/pharmacocinétique , Ritonavir/pharmacologie , Sulfonamides/pharmacologie , Sulfonamides/pharmacocinétique , Adulte , Aire sous la courbe , Carbamates/administration et posologie , Études croisées , Interactions médicamenteuses , Association de médicaments , Femelle , Furanes , Humains , Mâle , Adulte d'âge moyen , Organophosphates/administration et posologie , Ritonavir/administration et posologie , Sulfonamides/administration et posologieRÉSUMÉ
Fosamprenavir is one of the most recently approved HIV-1 protease inhibitors (PIs) and offers reductions in pill number and pill size, and omits the need for food and fluid requirements associated with the earlier-approved HIV-1 PIs. Three fosamprenavir dosage regimens are approved by the US FDA for the treatment of HIV-1 PI-naive patients, including fosamprenavir 1,400 mg twice daily, fosamprenavir 1,400 mg once daily plus ritonavir 200mg once daily, and fosamprenavir 700 mg twice daily plus ritonavir 100mg twice daily. Coadministration of fosamprenavir with ritonavir significantly increases plasma amprenavir exposure. The fosamprenavir 700 mg twice daily plus ritonavir 100mg twice daily regimen maintains the highest plasma amprenavir concentrations throughout the dosing interval; this is the only approved regimen for the treatment of HIV-1 PI-experienced patients and is the only regimen approved in the European Union. Fosamprenavir is the phosphate ester prodrug of the HIV-1 PI amprenavir, and is rapidly and extensively converted to amprenavir after oral administration. Plasma amprenavir concentrations are quantifiable within 15 minutes of dosing and peak at 1.5-2 hours after fosamprenavir dosing. Food does not affect the absorption of amprenavir following administration of the fosamprenavir tablet formulation; therefore, fosamprenavir tablets may be administered without regard to food intake. Amprenavir has a large volume of distribution, is 90% bound to plasma proteins and is a substrate of P-glycoprotein. With <1% of a dose excreted in urine, the renal route is not an important elimination pathway, while the principal route of amprenavir elimination is hepatic metabolism by cytochrome P450 (CYP) 3A4. Amprenavir is also an inhibitor and inducer of CYP3A4. Furthermore, fosamprenavir is commonly administered in combination with low-dose ritonavir, which is also extensively metabolised by CYP3A4, and is a more potent CYP3A4 inhibitor than amprenavir. This potent CYP3A4 inhibition contraindicates the coadministration of certain CYP3A4 substrates and requires others to be co-administered with caution. However, fosamprenavir can be co-administered with many other antiretroviral agents, including drugs of the nucleoside/nucleotide reverse transcriptase inhibitor, non-nucleoside reverse transcriptase inhibitor and HIV entry inhibitor classes. Coadministration with other HIV-1 PIs continues to be studied.The extensive fosamprenavir and amprenavir clinical drug interaction information provides guidance on how to co-administer fosamprenavir and fosamprenavir plus ritonavir with many other commonly co-prescribed medications, such as gastric acid suppressants, HMG-CoA reductase inhibitors, antibacterials and antifungal agents.
Sujet(s)
Carbamates/pharmacocinétique , Interactions médicamenteuses , Infections à VIH/traitement médicamenteux , Inhibiteurs de protéase du VIH/pharmacocinétique , VIH-1 (Virus de l'Immunodéficience Humaine de type 1) , Organophosphates/pharmacocinétique , Promédicaments/pharmacocinétique , Inhibiteurs de la transcriptase inverse/usage thérapeutique , Sulfonamides/pharmacocinétique , Adulte , Carbamates/sang , Carbamates/métabolisme , Furanes , Infections à VIH/métabolisme , Inhibiteurs de protéase du VIH/effets indésirables , Inhibiteurs de protéase du VIH/métabolisme , Période , Humains , Absorption intestinale , Organophosphates/métabolisme , Organophosphates/usage thérapeutique , Promédicaments/métabolisme , Inhibiteurs de la transcriptase inverse/pharmacocinétique , Inhibiteurs de la transcriptase inverse/pharmacologie , Sulfonamides/sang , Sulfonamides/métabolisme , Sulfonamides/usage thérapeutique , Distribution tissulaireRÉSUMÉ
High-dose combinations of fosamprenavir (FPV) and ritonavir (RTV) were evaluated in healthy adult subjects in order to select doses for further study in multiple protease inhibitor (PI)-experienced patients infected with human immunodeficiency virus type 1. Two high-dose regimens, FPV 1,400 mg twice a day (BID) plus RTV 100 mg BID and FPV 1,400 mg BID plus RTV 200 mg BID, were planned to be compared to the approved regimen, FPV 700 mg BID plus RTV 100 mg BID, in a randomized three-period crossover study. Forty-two healthy adult subjects were enrolled, and 39 subjects completed period 1. Due to marked hepatic transaminase elevations, predominantly with FPV 1,400 mg BID plus RTV 200 mg BID, the study was terminated prematurely. For FPV 1,400 mg BID plus RTV 100 mg BID, the values for plasma amprenavir (APV) area under the concentration-time profile over the dosing interval (tau) at steady state [AUC(0-tau)], maximum concentration of drug in plasma (C(max)), and plasma concentration at the end of tau at steady state (C(tau)) were 54, 81, and 26% higher, respectively, and the values for plasma RTV AUC(0-tau), C(max), and C(tau) were 49% higher, 71% higher, and 11% lower, respectively, than those for FPV 700 mg BID plus RTV 100 mg BID. For FPV 1,400 mg BID plus RTV 200 mg BID, the values for plasma APV AUC(0-tau), C(max), and C(tau) were 26, 48, and 32% higher, respectively, and the values for plasma RTV AUC(0-tau), C(max), and C(tau) increased 4.15-fold, 4.17-fold, and 3.99-fold, respectively, compared to those for FPV 700 mg BID plus RTV 100 mg BID. FPV 1,400 mg BID plus RTV 200 mg BID is not recommended due to an increased rate of marked hepatic transaminase elevations and lack of pharmacokinetic advantage. FPV 1,400 mg BID plus RTV 100 mg BID is currently under clinical evaluation in multiple PI-experienced patients.
Sujet(s)
Inhibiteurs de protéase du VIH/pharmacocinétique , Organophosphates/pharmacocinétique , Ritonavir/pharmacocinétique , Sulfonamides/pharmacocinétique , Adolescent , Adulte , Carbamates , Essais cliniques comme sujet , Études croisées , Relation dose-effet des médicaments , Association de médicaments , Femelle , Furanes , Inhibiteurs de protéase du VIH/effets indésirables , Inhibiteurs de protéase du VIH/sang , Séronégativité VIH , Humains , Mâle , Adulte d'âge moyen , Organophosphates/effets indésirables , Organophosphates/sang , Ritonavir/effets indésirables , Ritonavir/sang , Sulfonamides/effets indésirables , Sulfonamides/sangRÉSUMÉ
Chronic hepatitis C virus (HCV) infection is usually asymptomatic in children, but significant liver disease may occur. We evaluated the efficacy, safety, and pharmacokinetics of interferon alfa-2b and ribavirin in children with chronic HCV. We determined the optimal ribavirin dose in an initial cohort of a phase 1 study and then subsequently used it, in combination with interferon alfa-2b, in a second cohort of this study and a phase 3 trial. The primary efficacy endpoint in all studies was sustained virological response, defined by undetectable serum HCV RNA 24 weeks after completion of therapy. All efficacy and safety analyses were performed on the intent-to-treat population. Children receiving interferon alfa-2b plus ribavirin 15 mg/kg/d in the phase 1 study had the maximum reduction in serum HCV RNA at treatment weeks 4 and 12 with an acceptable safety profile. This ribavirin dose was selected as optimal and used in all subsequent studies. In all, 46% (54/118) of optimally treated children achieved sustained virological response. Sustained virological response was significantly higher in children with HCV genotype 2/3 (84%) than in those with HCV genotype 1 (36%). Adverse events led to dose modification in 37 (31%) and discontinuation in 8 (7%). Multiple-dose interferon alfa-2b and ribavirin peak and trough concentrations and area-under-the-curve were similar between children and adults. In conclusion, interferon alfa-2b in combination with ribavirin is effective and safe in children with chronic hepatitis C virus.
Sujet(s)
Antiviraux/usage thérapeutique , Hépatite C chronique/traitement médicamenteux , Interféron alpha/usage thérapeutique , Ribavirine/usage thérapeutique , Adolescent , Antiviraux/administration et posologie , Antiviraux/effets indésirables , Antiviraux/pharmacocinétique , Taille/effets des médicaments et des substances chimiques , Poids/effets des médicaments et des substances chimiques , Enfant , Enfant d'âge préscolaire , Relation dose-effet des médicaments , Association de médicaments , Femelle , Hepacivirus/génétique , Hépatite C chronique/métabolisme , Hépatite C chronique/virologie , Humains , Interféron alpha-2 , Interféron alpha/administration et posologie , Interféron alpha/effets indésirables , Interféron alpha/pharmacocinétique , Mâle , ARN viral/sang , Protéines recombinantes , Ribavirine/administration et posologie , Ribavirine/effets indésirables , Ribavirine/pharmacocinétique , Résultat thérapeutiqueRÉSUMÉ
OBJECTIVE: Delavirdine is a non-nucleoside reverse transcriptase inhibitor used in combination regimens for the treatment of HIV-1 infection. Our objective was to characterise the population pharmacokinetics of delavirdine in HIV-infected patients who participated in the adult AIDS Clinical Trials Group (ACTG) 260 and 261 studies. METHODS: ACTG 261 was a randomised, double-blind study of delavirdine 400mg three times daily, in various combination regimens; ACTG 260 was a concentration-targeted monotherapy study. Two hundred and thirty-four patients, and 1254 and 1251 plasma concentrations for delavirdine and N-delavirdine, respectively, were available for population pharmacokinetic analysis. The pharmacokinetic model (and initial parameters), based on previous studies, included two compartments for delavirdine (peripheral and central) and parallel clearance pathways (nonlinear conversion to N-delavirdine and first order clearance from the body). The model was one compartment for N-delavirdine with first order clearance. Diurnal variation of delavirdine and N-delavirdine oral clearance was modelled as a cosine function, with amplitude variation a fitted parameter. Pharmacokinetic parameter estimates were derived from iterative two-stage analysis; observed delavirdine and N-delavirdine concentrations fit with weighting by the inverse observation variance. Covariates were analysed by multiple general linear modelling. RESULTS: The mean (percent coefficient of variation [%CV]) CD4 count was 315 (109) cells/mm(3), weight 76.9 (14.7) kg, age 37 (8.5) years, and 15% of the population were women. Mean (%CV) population pharmacokinetic parameter estimates for delavirdine were: volume of distribution at steady state 67.6 (100) L, intrinsic oral clearance 19.8 (64) L/h, concentration at half the maximum velocity of metabolism (V(max)) 6.3 (69) micromol/L and first order oral clearance 0.57 (86) L/h. For N-delavirdine, the mean (%CV) apparent volume of distribution was 24.7 (75) L and apparent clearance 29.7 (42) L/h. The mean V(max) was 1376 (68) mg/day. The final model for average intrinsic clearance of delavirdine included race, sex, weight and age as significant covariates (p < 0.05); however, these covariates do not explain a significant proportion of the overall variability in the population. CONCLUSIONS: Delavirdine disposition exhibits nonlinear pharmacokinetics and large interpatient variability, and is significantly altered by time of day (impacting potential therapeutic drug monitoring and future pharmacokinetic study designs). Although race and sex appear to influence delavirdine pharmacokinetics, men and women and patients of different races should receive similar mg/kg dosage regimens. The presence of large interpatient variability supports the further investigation of the utility of therapeutic drug monitoring for delavirdine, if target drug concentrations can be better defined.
Sujet(s)
Agents antiVIH/pharmacocinétique , Carbamazépine/analogues et dérivés , Délavirdine/pharmacocinétique , Infections à VIH/métabolisme , Adolescent , Adulte , Agents antiVIH/métabolisme , Agents antiVIH/usage thérapeutique , Poids , Délavirdine/métabolisme , Délavirdine/usage thérapeutique , Méthode en double aveugle , Association de médicaments , Femelle , Infections à VIH/traitement médicamenteux , Humains , Mâle , Taux de clairance métabolique , Adulte d'âge moyen , , Facteurs sexuelsRÉSUMÉ
Twelve methadone-maintained HIV-negative subjects were given saquinavir/ritonavir (SQV/rtv) 1600 mg/100 mg once daily for 14 days. Pharmacokinetic evaluations of total and unbound methadone enantiomers (R and S) were conducted before and after SQV/rtv. SQV/rtv was well tolerated, with no ACTG Grade 3-4 adverse events, no evidence of sedation, and no changes in methadone dose. For R-methadone (active isomer), C(max), AUC(0-24 h), and C(min) were unchanged, but percent unbound 4 hours after dosing was reduced by 12%. For S-methadone, no differences in pharmacokinetic parameters of total drug were seen, but unbound concentrations were reduced by 15% and 21% at 4 and 24 hours after dosing, respectively. SQV trough concentrations exceeded the anticipated EC(50) (50 ng/mL) in 10/12 subjects, persisting for at least 6 hours after the final dose in 4/6 subjects. Once-daily SQV/rtv in methadone-maintained subjects is safe and not associated with any clinically significant interaction with methadone during 14 days of concomitant administration.