RESUMO
BACKGROUND: H4 receptor antagonists are potential novel treatments for inflammatory skin diseases, including atopic dermatitis (AD). OBJECTIVE: We sought to study the efficacy and safety of ZPL-3893787 (a selective H4 receptor antagonist) in patients with moderate-to-severe AD. METHODS: A randomized, double-blind, placebo-controlled, parallel-group study was conducted to evaluate ZPL-3893787 (30 mg) once-daily oral therapy in adults with moderate-to-severe AD. Patients were randomized (2:1) to ZPL-3893787 (n = 65) or placebo (n = 33) for 8 weeks. Patients had a history of AD for more than 12 months, Eczema Area and Severity Index (EASI) scores of 12 or greater and 48 or less, Investigator's Global Assessment (IGA) scores of 3 or greater, pruritus scores of 5 or greater (0- to 10-point scale), and AD on 10% or greater of body surface area. Efficacy parameters included EASI, IGA, SCORAD, and pruritus assessment. RESULTS: Treatment with oral ZPL-3893787 showed a 50% reduction in EASI score compared with 27% for placebo. The placebo-adjusted reduction in EASI score at week 8 was 5.1 (1-sided P = .01). Clear or almost-clear IGA scores were 18.5% with ZPL-3893787 versus 9.1% with placebo. SCORAD scores exhibited 41% reduction with ZPL-3893787 versus 26% with placebo (placebo-adjusted reduction of 10.0, P = .004). There was a 3-point reduction (scale, 1-10) in pruritus with ZPL-3893787, but there was a similar reduction with placebo, resulting in a nonsignificant difference (P = .249). Patient-reported pruritus subscores obtained from SCORAD were reduced with ZPL-3893787 compared with placebo at week 8 (nonsignificant). ZPL-3893787 was well tolerated. CONCLUSION: For the first time, these results showed that ZPL-3893787 improved inflammatory skin lesions in patients with AD, confirming H4 receptor antagonism as a novel therapeutic option.
Assuntos
Anti-Inflamatórios/uso terapêutico , Dermatite Atópica/tratamento farmacológico , Pirimidinas/uso terapêutico , Pirrolidinas/uso terapêutico , Adulto , Anti-Inflamatórios/farmacologia , Bélgica , Método Duplo-Cego , Feminino , Alemanha , Humanos , Masculino , Pessoa de Meia-Idade , Placebos , Polônia , Pirimidinas/farmacologia , Pirrolidinas/farmacologia , Receptores Histamínicos H4/antagonistas & inibidores , Resultado do Tratamento , Reino Unido , Adulto JovemRESUMO
PF-184298 ((S)-2,3-dichloro-N-isobutyl-N-pyrrolidin-3-ylbenzamide) and PF-4776548 ((3-(4-fluoro-2-methoxy-benzyl)-7-hydroxy-8,9-dihydro-3H,7H-pyrrolo[2,3-c][1,7]naphthyridin-6-one)) are novel compounds which were selected to progress to human studies. Discordant human pharmacokinetic predictions arose from pre-clinical in vivo studies in rat and dog, and from human in vitro studies, resulting in a clearance prediction range of 3 to >20 mL min⻹ kg⻹ for PF-184298, and 5 to >20 mL min⻹ kg⻹ for PF-4776548. A package of work to investigate the discordance for PF-184298 is described. Although ultimately complementary to the human pharmacokinetic data in characterising the disposition of PF-184298 in humans, these data did not provide any further confidence in pharmacokinetic prediction. A fit for purpose human pharmacokinetic study was conducted for each compound, with an oral pharmacologically active dose for PF-184298, and an intravenous and oral microdose for PF-4776548. This provided a relatively low cost, clear decision making approach, resulting in the termination of PF-4776548 and further progression of PF-184298. A retrospective analysis of the data showed that, if the tools had been available at the time, the pharmacokinetics of PF-184298 in human could have been predicted from a population based simulation tool in combination with physicochemical properties and in vitro human intrinsic clearance.
Assuntos
Anilidas/farmacocinética , Avaliação Pré-Clínica de Medicamentos/métodos , Modelos Biológicos , Naftiridinas/farmacocinética , Pirrolidinas/farmacocinética , Adulto , Anilidas/administração & dosagem , Alternativas aos Testes com Animais , Animais , Cães , Descoberta de Drogas , Humanos , Masculino , Microssomos Hepáticos/metabolismo , Naftiridinas/administração & dosagem , Farmacocinética , Pirrolidinas/administração & dosagem , Ratos , Inibidores Seletivos de Recaptação de Serotonina/administração & dosagem , Inibidores Seletivos de Recaptação de Serotonina/farmacocinética , Estatística como Assunto , Adulto JovemRESUMO
AIMS: Voriconazole is a novel triazole with broad-spectrum antifungal activity. It is likely that some patients receiving voriconazole may also require treatment with the anticoagulant warfarin. Cytochrome P450 isoenzymes are important in the metabolism of both these drugs. This study investigated the effect of voriconazole on the pharmacodynamics of warfarin by measuring prothrombin time, and also evaluated the safety and tolerability of the coadministered drugs. METHODS: This was a double-blind, placebo-controlled, two-way crossover study in which healthy male subjects received either 300 mg voriconazole or placebo twice daily on days 1-12, plus a single oral dose of 30 mg warfarin on day 7 of each study period. Volunteers were randomized to one of the following treatment sequences: voriconazole + warfarin followed by placebo + warfarin or placebo + warfarin followed by voriconazole + warfarin. There was a washout of at least of 7 days between treatment periods. RESULTS: The mean Cmax, AUCtau and tmax for voriconazole were 3736 ng ml-1, 25 733 ng.h ml-1, and 1.66 h, respectively. Both the mean maximum change from baseline prothrombin time and the mean area under the effect curve (AUEC) for prothrombin time during coadministration with voriconazole (17 s and 3211 s.h, respectively) were statistically significantly greater than the mean values observed during the placebo period (8 s and 2282 s.h ). Prothrombin times were still increased by a mean value of 5.4 s 144 h post warfarin dose following coadministration with voriconazole compared with a mean value of 0.6 s in the placebo treatment period. CONCLUSIONS: Coadministration of voriconazole and warfarin potentiates warfarin-induced prothrombin time prolongation. Regular monitoring of prothrombin time is recommended if these drugs are coadministered, with appropriate adjustment of the dose of warfarin.
Assuntos
Anticoagulantes/farmacologia , Antifúngicos/farmacologia , Tempo de Protrombina , Pirimidinas/farmacologia , Triazóis/farmacologia , Varfarina/farmacologia , Administração Oral , Adulto , Anticoagulantes/administração & dosagem , Anticoagulantes/efeitos adversos , Antifúngicos/efeitos adversos , Estudos Cross-Over , Método Duplo-Cego , Combinação de Medicamentos , Interações Medicamentosas , Sinergismo Farmacológico , Humanos , Masculino , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Triazóis/administração & dosagem , Triazóis/efeitos adversos , Voriconazol , Varfarina/administração & dosagem , Varfarina/efeitos adversosRESUMO
AIMS: Voriconazole is a triazole antifungal agent with potent fungicidal activity against Aspergillus species. Digoxin is a commonly prescribed cardiac glycoside with a narrow therapeutic index. This aim of this study was to investigate the effect of multiple-dose voriconazole on the steady-state pharmacokinetics of digoxin in healthy male volunteers. METHODS: This was a double-blind, randomized, placebo-controlled, parallel-group study. All subjects received daily administration of oral digoxin for a total of 22 days (0.5 mg twice daily on day 1, 0.25 mg twice daily on day 2 and 0.25 mg once daily on days 3-22). In addition, on days 11-22 the subjects were randomized to receive either voriconazole (200 mg twice daily) or matching placebo. RESULTS: Concomitant administration with voriconazole did not significantly alter the Cmax, AUCtau, tmax or CLR of digoxin at steady state. The ratios between groups for Cmax and AUCtau at day 22, corrected for baseline (day 10) were 109.8%[90% confidence interval (CI) 97.1, 124.1] and 100.5% (90% CI 91.4, 110.5), respectively. In addition, group mean Cmin values were similar in both treatment groups throughout the study. There were no significant differences between treatments with respect to the incidence of adverse events, all of which were classified as mild and transient in nature. CONCLUSIONS: The steady-state pharmacokinetics of digoxin are not affected in a clinically relevant manner by the concomitant administration of voriconazole.
Assuntos
Antifúngicos/farmacologia , Cardiotônicos/farmacocinética , Digoxina/farmacocinética , Pirimidinas/farmacologia , Triazóis/farmacologia , Administração Oral , Adulto , Antifúngicos/administração & dosagem , Antifúngicos/efeitos adversos , Área Sob a Curva , Cardiotônicos/administração & dosagem , Cardiotônicos/efeitos adversos , Digoxina/administração & dosagem , Digoxina/efeitos adversos , Método Duplo-Cego , Combinação de Medicamentos , Interações Medicamentosas , Humanos , Masculino , Plasma , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Triazóis/administração & dosagem , Triazóis/efeitos adversos , VoriconazolRESUMO
AIMS: Voriconazole, a new triazole antifungal agent, is metabolized mainly by cytochrome P450s CYP2C19 and CYP2C9, and also by CYP3A4. The aim of this open-label, placebo-controlled, randomized, three-way crossover study was to determine the effects of cimetidine and ranitidine on the steady-state pharmacokinetics of voriconazole. METHODS: Twelve healthy male subjects received oral voriconazole 200 mg twice daily plus cimetidine 400 mg twice daily, voriconazole 200 mg twice daily plus ranitidine 150 mg twice daily, and voriconazole 200 mg twice daily plus placebo twice daily. Treatment periods were separated by at least 7 days. RESULTS: When cimetidine was administered with voriconazole, the maximum plasma voriconazole concentration (Cmax) and the area under the plasma concentration-time curve of voriconazole (AUCtau) was increased by 18.3%[90% confidence interval (CI) 6.0, 32.0] and 22.5% (90% CI 13.3, 32.5), respectively. Concomitant ranitidine had no significant effect on voriconazole Cmax or AUCtau. Time of Cmax (tmax) elimination half-life (t 1/2) or terminal phase rate constant (kel) for voriconazole were similar in all three treatment groups. Most adverse events were mild and transitory; two subjects were withdrawn due to adverse events. CONCLUSIONS: Coadministration of the histamine H2-receptor antagonists cimetidine or ranitidine does not affect the steady-state pharmacokinetics of voriconazole in a clinically relevant manner.
Assuntos
Antifúngicos/farmacocinética , Cimetidina/farmacologia , Antagonistas dos Receptores H2 da Histamina/farmacologia , Pirimidinas/farmacocinética , Ranitidina/farmacologia , Triazóis/farmacocinética , Administração Oral , Adulto , Antifúngicos/administração & dosagem , Antifúngicos/efeitos adversos , Cimetidina/administração & dosagem , Cimetidina/efeitos adversos , Estudos Cross-Over , Combinação de Medicamentos , Interações Medicamentosas , Antagonistas dos Receptores H2 da Histamina/administração & dosagem , Antagonistas dos Receptores H2 da Histamina/efeitos adversos , Humanos , Masculino , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Ranitidina/administração & dosagem , Ranitidina/efeitos adversos , Triazóis/administração & dosagem , Triazóis/efeitos adversos , VoriconazolRESUMO
AIMS: Voriconazole is a new triazole antifungal agent, and is metabolized by the cytochrome P450 isoenzymes CYP2C9, CYP2C19 and to a lesser extent by CYP3A4. Protease inhibitors, such as indinavir, are also metabolized by cytochrome P450 (mainly CYP3A4). As these drugs are likely to be coadministered, these studies were performed to assess the pharmacokinetic interactions, safety and toleration of these drugs when taken together. METHODS: Two randomized placebo-controlled studies were conducted in healthy male volunteers. Study A was an open parallel-group study of the effect of indinavir on the steady-state pharmacokinetics of voriconazole in 18 volunteers (nine subjects in each group). Subjects received voriconazole 200 mg twice daily (days 1-7), then voriconazole 200 mg twice daily + indinavir 800 mg or placebo three times daily (days 8-17). Study B was a double-blind, randomized, two-way crossover study of the effect of voriconazole on the steady-state pharmacokinetics of indinavir in 14 volunteers. They received indinavir 800 mg three times daily + voriconazole 200 mg or placebo twice daily for two 7-day treatment periods separated by a washout period of at least 7 days. Pharmacokinetic parameters were compared within treatment groups at days 7 and 17 in Study A and between treatment groups on day 7 of each period in Study B. All adverse events were recorded. RESULTS: Study A: Seventeen subjects were evaluable for pharmacokinetic analysis (eight voriconazole + indinavir, nine voriconazole + placebo). The day 17/day 7 ratios for Cmax and AUCtau were estimated as 102%[90% confidence interval (CI) 91, 114] and 107% (90% CI 98, 118), respectively. Study B: Fourteen subjects were evaluable for pharmacokinetic analysis in each treatment period. The ratios between the geometric means for indinavir + voriconazole vs. indinavir + placebo were: Cmax, 91% (90% CI 83, 101), AUCtau, 87% (90% CI 77, 100), and Cmin, 101% (90% CI 82, 125). Trough plasma concentrations of indinavir were above the concentration required to inhibit HIV replication (IC95) in both treatment periods. Voriconazole coadministered with indinavir was well tolerated in both studies. CONCLUSIONS: The coadministration of voriconazole and indinavir in healthy volunteers had no clinically significant effect on the pharmacokinetics of either voriconazole or indinavir.
Assuntos
Antifúngicos/farmacocinética , Inibidores da Protease de HIV/farmacocinética , Indinavir/farmacocinética , Pirimidinas/farmacocinética , Triazóis/farmacocinética , Administração Oral , Adulto , Antifúngicos/administração & dosagem , Antifúngicos/efeitos adversos , Estudos Cross-Over , Combinação de Medicamentos , Interações Medicamentosas , Inibidores da Protease de HIV/administração & dosagem , Inibidores da Protease de HIV/efeitos adversos , Humanos , Indinavir/administração & dosagem , Indinavir/efeitos adversos , Masculino , Pessoa de Meia-Idade , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Triazóis/administração & dosagem , Triazóis/efeitos adversos , VoriconazolRESUMO
AIMS: Voriconazole is a new triazole with broad-spectrum antifungal activity against clinically significant and emerging pathogens. These studies evaluated the pharmacokinetics and safety of intravenous voriconazole in healthy male volunteers. METHODS: Two single-blind, placebo-controlled studies were conducted. In Study A, 12 subjects were randomized to voriconazole (3 mg kg-1) or placebo, administered once daily on days 1 and 12, and every 12 h on days 3-11. In Study B, 18 subjects were randomized to voriconazole or placebo, with voriconazole being administered as a loading dose at 6 mg kg-1 twice on day 1, then at 3 mg kg-1 twice daily on days 2-9, and once at 3 mg kg-1 on day 10. RESULTS: In both studies, the plasma concentrations of voriconazole increased rapidly following the initiation of dosing. Minimum observed plasma concentration (Cmin) values at steady state were above the in vitro minimum inhibitory concentrations (MICs) for most fungal pathogens (Cmin > 0.8 micro g ml-1). The use of a loading dose in Study B resulted in a shorter time to steady-state Cmin values than was observed in Study A. Values of the final day plasma pharmacokinetic parameters in Studies A and B were similar: maximum observed plasma concentration (Cmax) 3621 and 3063 ng ml-1; areas under the plasma concentration-time curve from time zero to the end of the dosing interval (AUCtau) 16 535 and 13 245 ng.h ml-1, and terminal elimination phase half-lives (t1/2) 6.5 and 6.7 h, respectively. On multiple dosing, voriconazole accumulated (AUCtau accumulation ratio 2.53-3.17, Study A) at a level that was not predictable from single-dose data. The mean concentration-time profiles for voriconazole in saliva were similar to those in plasma. Multiple doses of voriconazole were well tolerated and no subject discontinued from either study. Seven cases of possibly drug-related visual disturbance were reported in three subjects (Study B). CONCLUSIONS: Administration of a loading dose of 6 mg kg-1 i.v. voriconazole on the first day of treatment followed by 3 mg kg-1 i.v. twice daily achieves steady state by the third day of dosing. This dosage regimen results in plasma levels of the drug that rapidly exceed the minimum inhibitory concentrations (MICs) against important fungal pathogens, including Aspergillus spp.
Assuntos
Antifúngicos/farmacocinética , Pirimidinas/farmacocinética , Triazóis/farmacocinética , Adolescente , Adulto , Antifúngicos/administração & dosagem , Área Sob a Curva , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Plasma , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Saliva/química , Método Simples-Cego , Triazóis/administração & dosagem , Triazóis/efeitos adversos , VoriconazolRESUMO
AIMS: Voriconazole is a potent new triazole with broad-spectrum antifungal activity against clinically significant and emerging pathogens. The present study evaluated the safety, toleration, and pharmacokinetics of oral voriconazole after single and multiple dosing. METHODS: Sixty-four healthy subjects were randomized to receive treatment and 56 completed the study. Groups of eight subjects each received voriconazole doses of 2 mg kg-1 twice daily, 4 mg kg-1 once daily, 2 mg kg-1 three times daily, or 3 mg kg-1 twice daily. Eleven subjects received 1.5 mg kg-1 three times daily, and 21 subjects were administered placebo. RESULTS: Voriconazole exhibited nonlinear (dose- and time-dependent) pharmacokinetics. This deviation from linear pharmacokinetics was confirmed by linearity ratios of > 1 and decreasing kel values on multiple dosing, with a consequent increase in the terminal phase t1/2. There was also notable intersubject variability in Cmax and AUCtau. The absorption of voriconazole was rapid (mean tmax= 0.9-1.7 h) after single and multiple dosing and the decline in plasma concentration-time curves after tmax was generally biphasic. By day 12, the Cmax, AUCtau, tmax, and t1/2 values for the 3 mg kg-1 twice-daily group were 2356 ng ml-1, 11 170 ng.h ml-1, 1.1 h, and 6.4 h, respectively. The observed accumulation of voriconazole after multiple dosing was greater than predicted from single-dose data. Accumulation ratios for Cmax and AUCtau, which were 1.97 and 3.55, respectively, for the group given voriconazole 3 mg kg-1 twice daily, varied between treatment groups and appeared to be influenced by total daily dose and the frequency and duration of dosing. Visual inspection of Cmin values together with statistical analyses of Cmax and AUCtau values suggest that steady-state levels were achieved by the fifth to sixth day of multiple dosing. Plasma concentrations of voriconazole were well above the minimum inhibitory concentrations (MICs) for Aspergillus spp., Candida spp., and for most emerging fungal pathogens (Cmin > 0.8 micro g ml-1). Voriconazole was well tolerated: most treatment-related adverse events (abnormal vision, headache, dizziness) were mild and resolved within an hour of dosing. CONCLUSIONS: The oral dosing regimen selected for subsequent Phase II/III clinical trials on the basis of these results was 200 mg twice daily, equivalent to 3 mg kg-1 twice daily.
Assuntos
Antifúngicos/farmacocinética , Pirimidinas/farmacocinética , Triazóis/farmacocinética , Administração Oral , Adolescente , Adulto , Antifúngicos/administração & dosagem , Antifúngicos/efeitos adversos , Relação Dose-Resposta a Droga , Humanos , Masculino , Pessoa de Meia-Idade , Plasma , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Método Simples-Cego , Triazóis/administração & dosagem , Triazóis/efeitos adversos , VoriconazolRESUMO
AIMS: Voriconazole is a new triazole antifungal agent with activity against a range of clinically important and emerging pathogens. This study determined the effect of food on the pharmacokinetics of voriconazole in healthy volunteers. METHODS: This was an open, randomized, two-way crossover, multiple-dose study in male volunteers. Twelve subjects received voriconazole 200 mg twice daily for 6.5 days. Each dose was administered either with food or in the fasted state, i.e. not within 2 h of food. Treatment periods were separated by a minimum 7-day washout period. Plasma samples were taken for the estimation of voriconazole plasma concentrations on days 1 and 7. Safety and toleration were assessed by monitoring of both laboratory safety tests and adverse events. RESULTS: Administering voriconazole with food significantly decreased both day 7 AUCtau and Cmax by approximately 35% (9598-7520 ng.h ml-1; P = 0.003) and 22% (2038-1332 ng ml-1; P = 0.008), respectively. Administering voriconazole with food statistically significantly delayed absorption, evident from tmax values; the mean difference for tmax on day 7 was 1.1 h. The terminal phase rate constant was unchanged by administering voriconazole with food. The fasted terminal phase half-life was 7.3 h compared with 6.6 h for the fed state. Visual inspection of Cmin values suggests that steady state was achieved after 5 days in both dietary states. Voriconazole accumulation, as assessed by ratios of Cmax and AUCtau on days 1 and 7, was statistically significantly greater when administered with food (Cmax, P = 0.010, AUCtau, P = 0.006). Mean Cmax accumulation in the fasted state was 2.1-fold compared with 3.5-fold in the fed state. AUCtau accumulation in the fasted state was 3.1-fold compared with 4.2-fold in the fed state. There were no discontinuations due to adverse events or laboratory abnormalities. Treatment-related mild-to-moderate visual disturbances were experienced by six out of 12 subjects. CONCLUSIONS: The bioavailability of twice-daily 200 mg voriconazole is reduced by approximately 22% as measured by AUCtau after multiple dosing when taken with food, compared with fasting.
Assuntos
Antifúngicos/farmacocinética , Alimentos , Pirimidinas/farmacocinética , Triazóis/farmacocinética , Administração Oral , Adulto , Antifúngicos/administração & dosagem , Antifúngicos/efeitos adversos , Área Sob a Curva , Disponibilidade Biológica , Estudos Cross-Over , Interações Alimento-Droga , Humanos , Absorção Intestinal , Masculino , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Fatores de Tempo , Triazóis/administração & dosagem , Triazóis/efeitos adversos , VoriconazolRESUMO
AIMS: The antibiotic erythromycin is a potent inhibitor of cytochrome P450 CYP3A4 metabolism. As CYP isozymes, including CYP3A4, are involved in the metabolism of the new triazole voriconazole, this study investigated the effects of multiple-dose erythromycin or azithromycin on the steady-state pharmacokinetics of voriconazole in healthy male subjects. METHODS: In an open, randomized, parallel-group, single-centre study, 30 healthy male subjects aged 20-41 years received oral voriconazole 200 mg twice daily for 14 days plus either erythromycin (1 g twice daily on days 8-14), azithromycin (500 mg once daily on days 12-14) or placebo (twice daily on days 8-14). Only morning doses were administered on day 14. Plasma concentrations of voriconazole were measured up to 12 h postdose on days 7 and 14, and plasma pharmacokinetic parameters were calculated. Adverse events and standard laboratory test results were recorded before and throughout the study. RESULTS: Comparison of the voriconazole Cmax day 14/day 7 ratio for the voriconazole + erythromycin group with that of the voriconazole + placebo group yielded a ratio of 107.7%[90% confidence interval (CI) 90.6, 128.0]; for the voriconazole + azithromycin group, the ratio was 117.5% (90% CI 98.8, 139.7). Comparison of the voriconazole AUCtau day 14/day 7 ratios of the voriconazole + erythromycin and voriconazole + azithromycin groups with that of the voriconazole + placebo group showed ratios of 101.2% (90% CI 89.1, 114.8) and 107.9% (90% CI 95.1, 122.4), respectively. For voriconazole tmax, the differences between the day 14-day 7 calculations for the voriconazole + erythromycin or the voriconazole + azithromycin groups and that of the voriconazole + placebo group were - 0.2 h (90% CI - 0.8, 0.3) and - 0.1 h (90% CI - 0.7, 0.5), respectively. None of these changes was considered clinically relevant. The study drugs were well tolerated by subjects in all groups; the most common study drug-related adverse events were visual disturbances, reported in all groups, and abdominal pain, present in the voriconazole + erythromycin group. CONCLUSIONS: Coadministration of erythromycin or azithromycin does not affect the steady-state pharmacokinetics of voriconazole in a clinically relevant manner in healthy male subjects.
Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacocinética , Azitromicina/farmacologia , Eritromicina/farmacologia , Pirimidinas/farmacocinética , Triazóis/farmacocinética , Adulto , Antibacterianos/administração & dosagem , Antibacterianos/efeitos adversos , Antifúngicos/administração & dosagem , Antifúngicos/efeitos adversos , Área Sob a Curva , Azitromicina/administração & dosagem , Azitromicina/efeitos adversos , Combinação de Medicamentos , Interações Medicamentosas , Eritromicina/administração & dosagem , Eritromicina/efeitos adversos , Humanos , Masculino , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Triazóis/administração & dosagem , Triazóis/efeitos adversos , VoriconazolRESUMO
AIMS: Voriconazole is a new triazole antifungal agent, and is metabolized by the cytochrome P450 isoenzymes CYP2C9, CYP2C19, and, to a lesser extent, by CYP3A4. Phenytoin is an inducer of CYP3A4 activity, and a substrate and inducer of CYP2C9 and CYP2C19. The present studies investigated the pharmacokinetic interactions of voriconazole and phenytoin when coadministered. METHODS: Two placebo-controlled parallel-group studies were conducted in healthy male volunteers. Study A was an open-label study and investigated the effect of phenytoin (300 mg once daily) on the steady-state pharmacokinetics of voriconazole (200 mg and 400 mg twice daily). Study B was a double-blind randomized study to investigate the effects of voriconazole (400 mg twice daily) on the steady-state pharmacokinetics of phenytoin (300 mg once daily). Cmax and AUCtau were compared at days 7, 21, and 28 (Study A), and at days 7 and 17 (Study B). All adverse events were recorded. RESULTS: Study A: 21 subjects were evaluable (10 voriconazole + phenytoin, 11 voriconazole + placebo). For subjects receiving voriconazole (200 mg twice daily) plus phenytoin, the day 21/day 7 ratios for voriconazole Cmax and AUCtau were 60.7%[90% confidence interval (CI) 50.1, 73.6] and 35.9% (90% CI 29.7, 43.3), respectively. Adjusted for voriconazole + placebo, the ratios between the means were 50.7% (90% CI 38.8, 66.1) and 30.6% (90% CI 23.5, 39.7), respectively. When the dose of voriconazole was increased to 400 mg twice daily, the day 28/day 7 ratios for voriconazole Cmax and AUCtau were 134% (90% CI 89.2, 200) and 139% (90% CI 97.3, 199), respectively. Study B: 15 subjects were evaluable for pharmacokinetic assessments (six phenytoin + voriconazole, nine phenytoin + placebo). The ratios between the means for phenytoin + voriconazole/phenytoin + placebo on day 17 vs. day 7 were: phenytoin Cmax 167% (90% CI 144, 193) and phenytoin AUCtau 181% (90% CI 156, 210). All treatments were well tolerated: most adverse events were mild/moderate and transient. CONCLUSIONS: Repeat dose administration of phenytoin decreased the mean steady-state Cmax and AUCtau of voriconazole by approximately 50% and 70%, respectively. Increasing the dose of voriconazole from 200 mg to 400 mg b.d. compensated for this effect. Repeat dose administration of 400 mg b.d. voriconazole increased the mean steady-state Cmax and AUCtau of phenytoin by approximately 70% and 80%, respectively. It is therefore recommended that plasma phenytoin concentrations are monitored and the dose adjusted as appropriate when phenytoin is coadministered with voriconazole.
Assuntos
Anticonvulsivantes/farmacologia , Antifúngicos/farmacocinética , Fenitoína/farmacologia , Pirimidinas/farmacocinética , Triazóis/farmacocinética , Adulto , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/efeitos adversos , Antifúngicos/administração & dosagem , Antifúngicos/efeitos adversos , Combinação de Medicamentos , Interações Medicamentosas , Humanos , Masculino , Fenitoína/administração & dosagem , Fenitoína/efeitos adversos , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Triazóis/administração & dosagem , Triazóis/efeitos adversos , VoriconazolRESUMO
AIMS: Voriconazole, a novel triazole antifungal agent, is metabolized by the cytochrome P450 isoenzymes CYP2C19, CYP2C9, and to a lesser extent by CYP3A4. Omeprazole, a proton pump inhibitor used widely for the treatment of gastric and duodenal ulcers, is predominantly metabolized by CYP2C19 and CYP3A4. The aim of this study was to determine the effects of omeprazole on the steady-state pharmacokinetics of voriconazole. A secondary objective was to characterize the pharmacokinetic profile of an oral loading dose regimen of 400 mg twice-daily voriconazole on day 1. METHODS: This was an open, randomized, placebo-controlled, two-way crossover study of 18 healthy male volunteers. Subjects received oral voriconazole (400 mg twice daily on day 1 followed by 200 mg twice daily on days 2-9 and a single 200-mg dose on day 10) with either omeprazole (40 mg once daily) or matched placebo for 10 days. There was a minimum 7-day washout between treatment periods. RESULTS: Mean Cmax and AUCtau of voriconazole were increased by 15%[90% confidence interval (CI) 5, 25] and 41% (90% CI 29, 55), respectively, with no effect on tmax during coadministration of omeprazole. Visual inspection of predose plasma concentrations (Cmin) indicated that steady-state plasma concentrations were achieved following the second loading dose. One subject withdrew from the study during the voriconazole + omeprazole treatment period because of treatment-related abnormal liver function test values. All other treatment-related adverse events resolved without intervention. CONCLUSIONS: Omeprazole had no clinically relevant effect on voriconazole exposure, suggesting that no voriconazole dosage adjustment is necessary for patients in whom omeprazole therapy is initiated. Administration of a 400-mg twice-daily oral loading dose regimen on day 1 resulted in steady-state plasma levels of voriconazole being achieved following the second loading dose.