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1.
Br J Clin Pharmacol ; 89(5): 1690-1694, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-36537620

RESUMEN

Letermovir inhibits renal tubular organic anion transporter 3 (OAT3) in vitro and is predicted to inhibit OAT3 in vivo. Acyclovir, a substrate for OAT3, is likely to be coadministered with letermovir; therefore, letermovir may increase acyclovir concentrations. A drug-drug interaction study was conducted in healthy participants (N = 16) to assess the effect of letermovir on acyclovir pharmacokinetics. On Day 1, participants received a single oral dose of 400 mg acyclovir; on Days 2-7, participants received oral doses of 480 mg letermovir once daily with a single oral dose of 400 mg acyclovir coadministered on Day 7. Coadministration with letermovir resulted in geometric mean ratios (90% confidence intervals) for acyclovir area under the concentration-time curve from administration to infinity and maximum plasma concentration of 1.02 (0.87-1.20) and 0.82 (0.71-0.93), respectively. No notable safety issues were reported. No clinically significant interaction was observed between letermovir and acyclovir in healthy participants and no dose adjustment is required for coadministration.


Asunto(s)
Aciclovir , Humanos , Aciclovir/efectos adversos , Voluntarios Sanos , Interacciones Farmacológicas , Área Bajo la Curva
2.
Br J Clin Pharmacol ; 89(7): 2122-2130, 2023 07.
Artículo en Inglés | MEDLINE | ID: mdl-36717270

RESUMEN

AIMS: Letermovir, a cytomegalovirus (CMV) DNA terminase complex inhibitor, is a substrate of ABCB1 (P-glycoprotein; P-gp), organic anion transporting polypeptide (OATP)1B1/3, UDP-glucuronosyltransferase (UGT)1A1, UGT1A3 and possibly ABCG2 (breast cancer resistance protein; BCRP). A study was conducted to evaluate the effects of itraconazole, a prototypic ABCB1/ABCG2 inhibitor, on letermovir pharmacokinetics (PK) and the effects of letermovir on itraconazole PK. METHODS: In an open-label, fixed-sequence study in 14 healthy participants, 200 mg oral itraconazole was administered once daily for 4 days. Following a 10-day washout, 480 mg oral letermovir was administered once daily for 14 days (Days 1-14) and then coadministered with 200 mg itraconazole once daily for 4 days (Days 15-18). Intensive PK sampling was performed for letermovir and itraconazole. PK and safety were evaluated. RESULTS: Letermovir geometric mean ratio (GMR; 90% confidence interval [CI]) for area under the concentration-time curve from time 0 to 24 h (AUC0-24 ) was 1.33 (1.17, 1.51) and for maximum concentration (Cmax ) was 1.21 (1.05, 1.39) following administration with/without itraconazole. Itraconazole GMR (90% CI) for AUC0-24 was 0.76 (0.71, 0.81) and for Cmax was 0.84 (0.76, 0.92) following administration with/without letermovir. Coadministration of letermovir with itraconazole was generally well tolerated. CONCLUSIONS: The increase in letermovir exposure with coadministration of itraconazole is likely predominantly due to inhibition of intestinal ABCB1 and potentially ABCG2 transport. The mechanism for the decrease in itraconazole exposure is unknown. The modest changes in letermovir and itraconazole PK are not considered clinically meaningful.


Asunto(s)
Itraconazol , Proteínas de Neoplasias , Humanos , Itraconazol/efectos adversos , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2 , Acetatos/efectos adversos , Interacciones Farmacológicas , Área Bajo la Curva , Voluntarios Sanos
3.
J Pharmacokinet Pharmacodyn ; 47(5): 473-484, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32647957

RESUMEN

To develop a framework for evaluating the resorption effects of Cathepsin K (CatK) inhibitors and to inform dose regimen selection, a pharmacokinetic/pharmacodynamic (PK/PD) model for odanacatib (ODN) was developed based upon data from Phase 1 studies. Pooled PK/PD data from 11 studies (N = 249) were fit reasonably to a population inhibitory sigmoid Emax model. Body weight on E0 (baseline uNTx/Cr, urinary N-terminal telopeptide normalized by creatinine) and age on Emax (fractional inhibition of the biomarker response) were significant covariates for biomarker response. Simulations of typical osteoporosis patients (by age, sex and weight) indicated minimal differences between sexes in concentration-uNTx/Cr relationship. There was no evidence that regimen (daily vs. weekly dosing) influenced the PK/PD relationship of resorption inhibition for odanacatib. PK/PD models based on data from odanacatib (ODN) Phase 1 studies demonstrated that uNTx/Cr was an appropriate bone resorption biomarker for assessment of the effects of a CatK inhibitor. The models also identified the determinants of response in the PK/PD relationship for ODN (body weight on E0 and age on Emax).


Asunto(s)
Compuestos de Bifenilo/farmacocinética , Conservadores de la Densidad Ósea/farmacocinética , Resorción Ósea/prevención & control , Catepsina K/antagonistas & inhibidores , Adulto , Anciano , Biomarcadores/orina , Compuestos de Bifenilo/administración & dosificación , Compuestos de Bifenilo/efectos adversos , Conservadores de la Densidad Ósea/administración & dosificación , Conservadores de la Densidad Ósea/efectos adversos , Resorción Ósea/diagnóstico , Resorción Ósea/orina , Catepsina K/metabolismo , Creatinina/orina , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Monitoreo de Drogas/métodos , Femenino , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana Edad , Fragmentos de Péptidos/orina , Procolágeno/orina , Resultado del Tratamiento , Adulto Joven
4.
Br J Clin Pharmacol ; 85(6): 1072-1083, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-30663085

RESUMEN

Cathepsin K (CatK) is a cysteine protease abundantly expressed by osteoclasts and localized in the lysosomes and resorption lacunae of these cells. CatK is the principal enzyme responsible for the degradation of bone collagen. Odanacatib is a selective, reversible inhibitor of CatK at subnanomolar potency. The pharmacokinetics of odanacatib have been extensively studied and are similar in young healthy men, postmenopausal women and elderly men, and were qualitatively similar throughout Phase 1 development and in-patient studies. Following 3 weeks of 50 mg once weekly dosing the geometric mean area under the curve from 0 to 168 hours was 41.1 µM h, the concentration at 168 hours was 126 nM and the harmonic mean apparent terminal half-life was 84.8 hr. Odanacatib exposure increased in a less than dose proportional manner due to solubility limited absorption. It is estimated that approximately 70% of the absorbed dose of odanacatib is eliminated via metabolism, 20% is excreted as unchanged drug in the bile or faeces, and 10% is excreted as unchanged drug in the urine. The systemic clearance was low (approximately 13 mL/min). Odanacatib decreases the degradation of bone matrix proteins and reduces the efficiency of bone resorption with target engagement confirmed by a robust decrease in serum C-telopeptides of type 1 collagen (approximately 60%), urinary aminoterminal crosslinked telopeptides of type 1 collagen to creatinine ratio (approximately 50%) and total urine deoxypyridinoline/Cr (approximately 30%), with an increase in serum cross-linked carboxy-terminal telopeptide of type 1 collagen (approximately 55%). The 50-mg weekly dosing regimen evaluated in Phase 3 achieved near maximal reduction in bone resorption throughout the treatment period. The extensive clinical programme for odanacatib, together with more limited clinical experience with other CatK inhibitors (balicatib and ONO-5334), provides important insights into the clinical pharmacology of CatK inhibition and the potential role of CatK in bone turnover and mineral homeostasis. Key findings include the ability of this mechanism to: (i) provide sustained reductions in resorption markers, increases in bone mineral density, and demonstrated fracture risk reduction; (ii) be associated with relative formation-sparing effects such that sustained resorption reduction is achieved without accompanying meaningful reductions in bone formation; and (iii) lead to increases in osteoclast number as well as other osteoclast activity (including build-up of CatK enzyme), which may yield transient increases in resorption following treatment discontinuation and the potential for nonmonotonic responses at subtherapeutic doses.


Asunto(s)
Compuestos de Bifenilo/uso terapéutico , Conservadores de la Densidad Ósea/uso terapéutico , Remodelación Ósea/efectos de los fármacos , Huesos/efectos de los fármacos , Catepsina K/antagonistas & inhibidores , Inhibidores de Cisteína Proteinasa/uso terapéutico , Osteoporosis/tratamiento farmacológico , Animales , Compuestos de Bifenilo/efectos adversos , Compuestos de Bifenilo/farmacocinética , Conservadores de la Densidad Ósea/efectos adversos , Conservadores de la Densidad Ósea/farmacocinética , Huesos/enzimología , Huesos/fisiopatología , Catepsina K/metabolismo , Inhibidores de Cisteína Proteinasa/efectos adversos , Inhibidores de Cisteína Proteinasa/farmacocinética , Femenino , Humanos , Masculino , Osteoporosis/enzimología , Osteoporosis/patología , Transducción de Señal , Investigación Biomédica Traslacional , Resultado del Tratamiento
5.
Drug Metab Dispos ; 44(9): 1450-8, 2016 09.
Artículo en Inglés | MEDLINE | ID: mdl-27402726

RESUMEN

A stable-label i.v./oral study design was conducted to investigate the pharmacokinetics (PK) of odanacatib. Healthy, postmenopausal women received oral doses of unlabeled odanacatib administered simultaneously with a reference of 1 mg i.v. stable (13)C-labeled odanacatib. The absolute bioavailability of odanacatib was 30% at 50 mg (the phase 3 dose) and 70% at 10 mg, which is consistent with solubility-limited absorption. Odanacatib exposure (area under the curve from zero to infinity) increased by 15% and 63% when 50 mg was administered with low-fat and high-fat meals, respectively. This magnitude of the food effect is unlikely to be clinically important. The volume of distribution was ∼100 liters. The clearance was ∼0.8 l/h (13 ml/min), supporting that odanacatib is a low-extraction ratio drug. Population PK modeling indicated that 88% of individuals had completed absorption of >80% bioavailable drug within 24 hours, with modest additional absorption after 24 hours and periodic fluctuations in plasma concentrations contributing to late values for time to Cmax in some subjects.


Asunto(s)
Compuestos de Bifenilo/farmacocinética , Interacciones Alimento-Droga , Posmenopausia , Administración Oral , Anciano , Área Bajo la Curva , Disponibilidad Biológica , Compuestos de Bifenilo/administración & dosificación , Compuestos de Bifenilo/sangre , Estudios Cruzados , Femenino , Semivida , Humanos , Infusiones Intravenosas , Persona de Mediana Edad
6.
Int J Clin Pharmacol Ther ; 51(8): 688-92, 2013 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-23782582

RESUMEN

OBJECTIVES: This study was conducted in order to assess the effect of multiple doses of odanacatib, a cathepsin (Cat)-K inhibitor, on the pharmacokinetics of digoxin. MATERIALS: Twelve healthy male and female subjects received 0.5 mg digoxin and 50 mg odanacatib. METHODS: This open label study was conducted to determine the effect of odanacatib on the plasma pharmacokinetics of immunoreactive digoxin. Subjects received a single oral dose of 0.5 mg digoxin followed by a 10-day washout, followed by 3 once-weekly oral doses of 50 mg odanacatib and co-administration with 0.5 mg digoxin with the last odanacatib dose. A linear mixed-effect model was used to analyze AUC0-120h. Safety and tolerability were assessed. RESULTS: The estimated geometric-mean-ratio (90% confidence interval) for AUC0-120h was 0.95 (0.89, 1.01), which was within (0.80, 1.25) determined to demonstrate a lack of interaction. There were no serious AEs, discontinuations due to AEs, or clinically significant abnormalities in ECG or vital sign measurements. CONCLUSIONS: This study demonstrated that 50 mg odanacatib did not lead to clinically important effects on the pharmacokinetics of 0.5 mg digoxin.


Asunto(s)
Compuestos de Bifenilo/farmacología , Digoxina/farmacocinética , Adulto , Compuestos de Bifenilo/administración & dosificación , Compuestos de Bifenilo/efectos adversos , Digoxina/administración & dosificación , Digoxina/efectos adversos , Interacciones Farmacológicas , Femenino , Humanos , Masculino , Persona de Mediana Edad
7.
Clin Pharmacol Ther ; 111(3): 664-675, 2022 03.
Artículo en Inglés | MEDLINE | ID: mdl-34888851

RESUMEN

Rifampin has acute inhibitory and chronic inductive effects that can cause complex drug-drug interactions. Rifampin inhibits transporters including organic-anion-transporting polypeptide (OATP)1B and P-glycoprotein (P-gp), and induces enzymes and transporters including cytochrome P450 3A, UDP-glucuronosyltransferase (UGT)1A, and P-gp. This study aimed to separate inhibitory and inductive effects of rifampin on letermovir disposition and elimination (indicated for cytomegalovirus prophylaxis in hematopoietic stem cell transplant recipients). Letermovir is a substrate of UGT1A1/3, P-gp, and OATP1B, with its clearance primarily mediated by OATP1B. Letermovir (single-dose) administered with rifampin (single-dose) resulted in increased letermovir exposure through transporter inhibition. Chronic coadministration with rifampin (inhibition plus potential OATP1B induction) resulted in modestly decreased letermovir exposure vs. letermovir alone. Letermovir administered 24 hours after the last rifampin dose (potential OATP1B induction) resulted in markedly decreased letermovir exposure. These data suggest rifampin may induce transporters that clear letermovir; the modestly reduced letermovir exposure with chronic rifampin coadministration likely reflects the net effect of inhibition and induction. OATP1B endogenous biomarkers coproporphyrin (CP) I and glycochenodeoxycholic acid-sulfate (GCDCA-S) were also analyzed; their exposures increased after single-dose rifampin plus letermovir, consistent with OATP1B inhibition and prior reports of inhibition by rifampin alone. CP I and GCDCA-S exposures were substantially reduced with letermovir administered 24 hours after the last dose of rifampin vs. letermovir plus chronic rifampin coadministration. This study suggests that OATP1B induction may contribute to reduced letermovir exposure after chronic rifampin administration, although given the complexity of letermovir disposition alternative mechanisms are not fully excluded.


Asunto(s)
Acetatos/farmacocinética , Interacciones Farmacológicas/fisiología , Transportadores de Anión Orgánico/metabolismo , Quinazolinas/farmacocinética , Rifampin/administración & dosificación , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Adolescente , Adulto , Área Bajo la Curva , Biomarcadores/metabolismo , Coproporfirinas/metabolismo , Citocromo P-450 CYP3A/metabolismo , Femenino , Hepatocitos/metabolismo , Humanos , Transportador 1 de Anión Orgánico Específico del Hígado/metabolismo , Persona de Mediana Edad , Miembro 1B3 de la Familia de los Transportadores de Solutos de Aniones Orgánicos/metabolismo , Adulto Joven
8.
Clin Pharmacol Drug Dev ; 7(7): 744-750, 2018 09.
Artículo en Inglés | MEDLINE | ID: mdl-29443463

RESUMEN

Odanacatib (ODN), an oral selective inhibitor of cathepsin K, was an investigational agent previously in development for the treatment of osteoporosis. In this phase 1 open-label study, 12 healthy Chinese postmenopausal women received single-dose ODN 50 mg on day 1 and multiple-dose ODN 50 mg once weekly on days 15, 22, 29, and 36 under fasted conditions. Pharmacokinetic (PK) parameters were evaluated on days 1 and 36. Multiple-dose area under the concentration-time profile (AUC0-168h ) and maximum plasma concentration (Cmax ) were compared with historical data from 9 non-Chinese postmenopausal women who also received ODN 50 mg once weekly for 4 weeks. Median time to Cmax (tmax ) was 3 and 4 hours following single- and multiple-dose administration, respectively. The arithmetic mean ± SD terminal half-life was 81.0 ± 14.0 and 106.7 ± 14.4 hours following single- and multiple-dose administration, respectively. Comparison of multiple-dose PK parameters showed that the geometric mean ratios (Chinese/non-Chinese) and 95%CIs for AUC0-168h and Cmax were 0.81 (0.55-1.19) and 0.87 (0.69-1.11), respectively. All adverse events were mild, none were serious, and none led to discontinuation. Single- and multiple-dose PKs of ODN 50 mg in Chinese postmenopausal women were generally similar to those previously reported in non-Chinese postmenopausal women.


Asunto(s)
Compuestos de Bifenilo/administración & dosificación , Compuestos de Bifenilo/farmacocinética , Posmenopausia/sangre , Administración Oral , Anciano , Área Bajo la Curva , Pueblo Asiatico , Compuestos de Bifenilo/efectos adversos , Esquema de Medicación , Drogas en Investigación , Femenino , Semivida , Humanos , Persona de Mediana Edad , Posmenopausia/etnología
9.
J Clin Pharmacol ; 57(1): 110-117, 2017 01.
Artículo en Inglés | MEDLINE | ID: mdl-27321774

RESUMEN

This open-label 2-period study assessed the effect of multiple-dose administration of rifampin, a strong cytochrome P450 3A (CYP3A) and P-glycoprotein inducer, on the pharmacokinetics of odanacatib, a cathepsin K inhibitor. In period 1, 12 healthy male subjects (mean age, 30 years) received a single dose of odanacatib 50 mg on day 1, followed by a 28-day washout. In period 2, subjects received rifampin 600 mg/day for 28 days; odanacatib 50 mg was coadministered on day 14. Blood samples for odanacatib pharmacokinetics were collected at predose and on day 1 of period 1 and day 14 of period 2. Coadministration of odanacatib and rifampin significantly reduced odanacatib exposure. The odanacatib AUC0-∞ geometric mean ratio (90% confidence interval) of odanacatib + rifampin/odanacatib alone was 0.13 (0.11-0.16). The harmonic mean ± jackknife standard deviation apparent terminal half-life (t½ ) was 71.6 ± 10.2 hours for odanacatib alone and 16.0 ± 3.4 hours for odanacatib + rifampin, indicating greater odanacatib clearance following coadministration with rifampin. Samples were collected in period 2 during rifampin dosing (days 1, 14, and 28) and after rifampin discontinuation (days 35, 42, and 56) to evaluate the ratio of plasma 4ß-hydroxycholesterol to total serum cholesterol as a CYP3A4 induction biomarker; the ratio increased ∼5-fold over 28 days of daily dosing with 600 mg rifampin, demonstrating sensitivity to CYP3A4 induction.


Asunto(s)
Compuestos de Bifenilo/administración & dosificación , Compuestos de Bifenilo/sangre , Rifampin/administración & dosificación , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/sangre , Adulto , Inductores del Citocromo P-450 CYP3A/administración & dosificación , Esquema de Medicación , Interacciones Farmacológicas/fisiología , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven
10.
J Popul Ther Clin Pharmacol ; 20(3): e312-20, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-24142206

RESUMEN

BACKGROUND: Warfarin is an anticoagulant with a narrow therapeutic index that is involved in a number of drug-drug interactions. OBJECTIVES: This study evaluates the potential effect of odanacatib (a cathepsin K inhibitor in development for the treatment of osteoporosis) on the pharmacokinetics and pharmacodynamics of warfarin. METHODS: In a randomized, open-label, two-period fixed-sequence design, 13 healthy, postmenopausal female subjects received two different treatments (Treatment A: a single dose of 30 mg warfarin; Treatment B: 3 once-weekly doses of 50 mg odanacatib with 30 mg warfarin co-administered with the last dose). Warfarin R(+) and S(-) enantiomer concentrations and prothrombin time were measured at pre-dose and at specified time points over 168 hours in each treatment period. Statistical analysis was performed using linear mixed effects model. RESULTS: Odanacatib was generally well tolerated when co-administered with warfarin in this study. The GMRs (95% confidence intervals [CI]) for plasma AUC0-∞ of warfarin+odanacatib/warfarin alone were 0.99 (0.94, 1.03) for warfarin R(+) and 1.00 (0.97, 1.03) for warfarin S(-), consistent with a lack of interaction between odanacatib and warfarin; results for Cmax, Tmax, and terminal t½ provided also demonstrated no interaction. The GMR (warfarin + odancacatib/warfarin alone) and 95% CI for the statistical comparison of INR AUC(0-168 hr) was 1.01 (0.98, 1.04). CONCLUSIONS: The single dose pharmacokinetics and pharmacodynamics of orally administered warfarin were not meaningfully affected by multiple dose administration of odanacatib, indicating that odanacatib is not a clinically important inhibitor of CYPs 2C9, 3A4, 2C19, or 1A2.


Asunto(s)
Anticoagulantes/administración & dosificación , Anticoagulantes/farmacocinética , Compuestos de Bifenilo/administración & dosificación , Compuestos de Bifenilo/farmacocinética , Warfarina/administración & dosificación , Warfarina/farmacocinética , Anciano , Anticoagulantes/sangre , Compuestos de Bifenilo/sangre , Catepsina K/antagonistas & inhibidores , Catepsina K/sangre , Interacciones Farmacológicas/fisiología , Femenino , Humanos , Persona de Mediana Edad , Osteoporosis Posmenopáusica/sangre , Osteoporosis Posmenopáusica/prevención & control , Warfarina/sangre
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