ABSTRACT
AIM: The aim of the study was to simplify the dosing regimen of peginterferon alfa-2a in paediatric patients with chronic hepatitis C. METHODS: A population pharmacokinetic (PK) model was developed using PK data from 14 children aged 2-8 years and 402 adults. Simulations were produced to identify a simplified dosing regimen that would provide exposures similar to those observed in the paediatric clinical trials and in the range known to be safe/efficacious in adults. Model predictions were evaluated against observed adult and paediatric data to reinforce confidence of the proposed dosing regimen. RESULTS: The final model was a two compartment model with a zero order resorption process. Covariates included a linear influence of body surface area (BSA) on apparent oral clearance (CL/F) and a linear influence of body weight on apparent volume of distribution of the central compartment (V1 /F). A simplified dosing regimen was developed which is expected to provide exposures in children aged ≥5 years similar to the dosing formula used in the paediatric clinical trial and within the range that is safe/efficacious in adults. This simplified regimen is approved in the EU and in other countries for the treatment of chronic hepatitis C in treatment-naive children/adolescents aged ≥5 years in combination with ribavirin. CONCLUSION: Pre-existing adult PK data were combined with relatively limited paediatric PK data to develop a PK model able to predict exposure in both populations adequately. This provided increased confidence in characterizing PK in children and helped in the development of a simplified dosing regimen of peginterferon alfa-2a in paediatric patients.
Subject(s)
Antiviral Agents/administration & dosage , Drug Dosage Calculations , Hepatitis C/drug therapy , Interferon-alpha/administration & dosage , Models, Biological , Polyethylene Glycols/administration & dosage , Adolescent , Adult , Antiviral Agents/pharmacokinetics , Antiviral Agents/therapeutic use , Body Surface Area , Child , Child, Preschool , Clinical Trials as Topic , Computer Simulation , Drug Administration Schedule , Humans , Interferon-alpha/pharmacokinetics , Interferon-alpha/therapeutic use , Polyethylene Glycols/pharmacokinetics , Polyethylene Glycols/therapeutic use , Predictive Value of Tests , Recombinant Proteins/administration & dosage , Recombinant Proteins/pharmacokinetics , Recombinant Proteins/therapeutic use , Tissue Distribution , Young AdultABSTRACT
BACKGROUND AND AIM: Chronic hepatitis C is an important public health problem in Asia. We evaluated the safety, efficacy, and pharmacokinetics of fixed-dose ritonavir-boosted danoprevir plus peginterferon alfa-2a/ribavirin in treatment-naive Asian patients with chronic hepatitis C virus (HCV) genotype (G)1 infection. METHODS: Treatment-naive G1 patients in Taiwan, Thailand, and Korea with serum HCV-RNA level ≥ 105 IU/mL received ritonavir-boosted danoprevir 125/100 mg twice daily plus peginterferon alfa-2a/ribavirin for either 12 (noncirrhotic patients: Arm A, n = 34) or 24 weeks (cirrhotic patients: Arm B, n = 27) in this phase II open-label study. Sustained virologic response was defined as HCV-RNA < 25 IU/mL 12 weeks after end of treatment (SVR12). RESULTS: Similar SVR12 rates were achieved in Arms A (88.2%; 95% confidence interval, 73.4-95.3%) and B (88.9%; 71.9-96.2%). Most patients had G1b infection, among whom SVR12 rates in Arms A and B were 96.7% and 91.7%, respectively. The overall SVR12 rate was 94.0% in noncirrhotic Taiwanese patients (100% in the subset of G1b patients). No patients withdrew for safety reasons. Three (11%) cirrhotic patients (Arm B) experienced serious adverse events, none of which was considered to be related to treatment. No Grade 3/4 alanine aminotransferase elevations were reported. The pharmacokinetic properties of danoprevir were broadly overlapping in noncirrhotic and cirrhotic patients both on Days 1 and 14. CONCLUSIONS: Ritonavir-boosted danoprevir plus peginterferon alfa-2a/ribavirin produced sustained virologic response rates > 90% after 12 weeks' treatment in noncirrhotic and 24 weeks' treatment in cirrhotic Asian patients with G1b infection and was well tolerated. These regimens are well suited to countries where G1b predominates.
Subject(s)
Antiviral Agents/therapeutic use , Hepatitis C, Chronic/drug therapy , Liver Cirrhosis/drug therapy , Adult , Aged , Antiviral Agents/adverse effects , Antiviral Agents/blood , Cyclopropanes , Drug Therapy, Combination , Female , Hepacivirus/genetics , Hepacivirus/isolation & purification , Hepatitis C, Chronic/complications , Humans , Interferon-alpha/adverse effects , Interferon-alpha/blood , Interferon-alpha/therapeutic use , Isoindoles , Lactams/adverse effects , Lactams/blood , Lactams/therapeutic use , Lactams, Macrocyclic , Liver Cirrhosis/virology , Male , Middle Aged , Polyethylene Glycols/adverse effects , Polyethylene Glycols/therapeutic use , Proline/analogs & derivatives , RNA, Viral/blood , Recombinant Proteins/adverse effects , Recombinant Proteins/blood , Recombinant Proteins/therapeutic use , Ribavirin/adverse effects , Ribavirin/blood , Ribavirin/therapeutic use , Ritonavir/adverse effects , Ritonavir/blood , Ritonavir/therapeutic use , Sulfonamides/adverse effects , Sulfonamides/blood , Sulfonamides/therapeutic use , Young AdultABSTRACT
This work characterizes the pharmacokinetics (PK) of oseltamivir phosphate (OP) and its active metabolite, oseltamivir carboxylate (OC), and investigates oseltamivir i.v. dosing regimens for treatment of influenza in patients with normal renal function and with various degrees of renal impairment. Initially, data collected from 149 subjects with normal renal function and mild to severe renal impairment who were administered 40-200 mg oseltamivir i.v. were described by a four-compartment model. Two compartments described OP, one compartment described OC and one compartment described OP to OC metabolism. Then, data of 128 subjects administered 20-1,000 mg oseltamivir orally were added. The absorption model included three first-order processes with direct (via first-pass) input in the OC compartment and two (direct and delayed) inputs in the OP compartment. Simulations and PK bridging were used to recommend i.v. dosing regimens. The analysis demonstrated that renal function had a major effect on OC clearance (CL M ) and exposure. CL M for subjects with mild, moderate and severe renal impairment was 18, 50, and 84 % lower than for subjects with normal renal function. Simulations were used to select i.v. dosing regimens that provide OC Cmin coverage and exposures comparable to those achieved in subjects with normal renal function administered 75 mg b.i.d. orally. The oseltamivir dose depended on the degree of renal impairment and was independent of route of administration. Specifically, 75 mg b.i.d. is recommended for subjects with normal renal function or mild renal impairment, 30 mg b.i.d. for subjects with moderate renal impairment, and 30 mg q.d. for subjects with severe renal impairment. Recommended i.v. doses were the same as those recommended for oral administration in corresponding renal impairment groups.
Subject(s)
Kidney Diseases/drug therapy , Kidney Diseases/metabolism , Models, Biological , Oseltamivir/analogs & derivatives , Administration, Intravenous , Administration, Oral , Adolescent , Adult , Aged , Aged, 80 and over , Biological Availability , Female , Humans , Male , Middle Aged , Oseltamivir/administration & dosage , Oseltamivir/metabolism , Young AdultABSTRACT
BACKGROUND/AIMS: PROGRESS randomized chronic hepatitis C genotype 1 patients with a baseline viral load ≥400,000 IU/mL weighing ≥85 kg to regimens of 180 µg/week for 48 weeks or 360 µg/week for 12 weeks followed by 180 µg/week for 36 weeks peginterferon alfa-2a plus ribavirin. This analysis explored pharmacokinetics and early viral kinetics (VK) and evaluates differences between groups. METHODOLOGY: Blood samples for pharmacokinetic and VK analyses were collected from 51 patients enrolled in the PROGRESS study. RESULTS: Mean peginterferon alfa-2a trough concentration at week 12 was 11.7±4.3 ng/mL for 180 µg and 23.4±11.3 ng/mL for 360 µg. Early VK profiles suggested a trend towards an enhanced viral decline in the 360 µg groups with a mean decrease in HCV RNA at 48 hours post first dose of 1.04 log10 (IU/mL) compared with 0.76 log10 (IU/mL) in the 180 µg groups. Mean beta slope increased with dose, ranging from 0.38±0.26 log10 IU/week at 180 µg to 0.52±0.32 log10 IU/week at 360 µg. CONCLUSIONS: Early viral de clines may be enhanced with the 360 µg dose. These data may suggest the utility of high-dose peginterfer on alfa-2a plus direct-acting antivirals (DAA) in select difficult-to-treat populations.
Subject(s)
Antiviral Agents/administration & dosage , Antiviral Agents/pharmacokinetics , Hepacivirus/drug effects , Hepatitis C, Chronic/drug therapy , Interferon-alpha/administration & dosage , Interferon-alpha/pharmacokinetics , Polyethylene Glycols/administration & dosage , Polyethylene Glycols/pharmacokinetics , Ribavirin/administration & dosage , Ribavirin/pharmacokinetics , Adult , Antiviral Agents/blood , Biomarkers/blood , Drug Monitoring , Drug Therapy, Combination , Female , Hepacivirus/genetics , Hepatitis C, Chronic/diagnosis , Hepatitis C, Chronic/virology , Humans , Interferon-alpha/blood , Male , Middle Aged , RNA, Viral/blood , Recombinant Proteins/administration & dosage , Recombinant Proteins/blood , Recombinant Proteins/pharmacokinetics , Ribavirin/blood , Treatment Outcome , United States , Viral LoadABSTRACT
Danoprevir (DNV) is a hepatitis C virus (HCV) protease inhibitor that achieves high sustained virologic response (SVR) rates in combination with peginterferon alfa-2a-ribavirin in treatment-naive HCV genotype 1 (G1)-infected patients. This study explored the efficacy and safety of ritonavir-boosted DNV (DNVr) plus peginterferon alfa-2a-ribavirin in G1-infected prior peginterferon-ribavirin null responders. Null responders (<2-log10 reduction in HCV RNA level at week 12) were given an open-label combination of 100 mg of ritonavir and 100 mg of DNV (100/100 mg DNVr) every 12 h (q12h) plus peginterferon alfa-2a-ribavirin for 12 weeks. All patients achieving an early virologic response (EVR; ≥2-log10 decrease in HCV RNA by week 12) continued treatment with peginterferon alfa-2a-ribavirin; those without an EVR discontinued all study drugs. Twenty-four prior null responders were enrolled; 16 patients (67%) were infected with HCV G1b, and 8 (33%) were infected with G1a. Ninety-six percent of patients had an IL28B non-CC genotype. A sustained virologic response at 24 weeks posttreatment (SVR24) was achieved in 67% of patients, with a higher rate in G1b-infected (88%) than G1a-infected (25%) patients. Resistance-related breakthrough occurred in 4/8 G1a and 1/16 G1b patients through the DNV resistance-associated variant (RAV) NS3 R155K. NS3 R155K was also detected in 2/2 G1a patients who relapsed. Treatment was well tolerated. Two patients withdrew prematurely from study medications due to adverse events. Two serious adverse events were reported; both occurred after completion of DNVr therapy and were considered unrelated to treatment. No grade 3 or 4 alanine aminotransferase (ALT) elevations were observed. DNVr plus peginterferon alfa-2a-ribavirin demonstrated high SVR24 rates in HCV G1b-infected prior null responders and was well tolerated. (This study has been registered at ClinicalTrials.gov under registration no. NCT01185860.).
Subject(s)
Antiviral Agents/administration & dosage , Hepatitis C, Chronic/drug therapy , Interferon-alpha/administration & dosage , Lactams/administration & dosage , Polyethylene Glycols/administration & dosage , RNA, Viral/antagonists & inhibitors , Ribavirin/administration & dosage , Ritonavir/administration & dosage , Sulfonamides/administration & dosage , Adult , Alanine Transaminase/blood , Antiviral Agents/adverse effects , Cyclopropanes , Drug Administration Schedule , Drug Resistance, Viral/drug effects , Drug Therapy, Combination , Female , Genotype , Hepacivirus/drug effects , Hepacivirus/physiology , Hepatitis C, Chronic/virology , Humans , Interferon-alpha/adverse effects , Isoindoles , Lactams/adverse effects , Lactams, Macrocyclic , Male , Middle Aged , Mutation , Polyethylene Glycols/adverse effects , Proline/analogs & derivatives , RNA, Viral/genetics , Recombinant Proteins/administration & dosage , Recombinant Proteins/adverse effects , Ribavirin/adverse effects , Ritonavir/adverse effects , Sulfonamides/adverse effects , Treatment Outcome , Viral Load/drug effects , Viral Nonstructural Proteins/geneticsABSTRACT
BACKGROUND: Danoprevir is a potent, highly selective, macrocyclic, orally bioavailable inhibitor of the hepatitis C virus protease, and a substrate of cytochrome P450 (CYP) 3A. It is co-administered with low-dose ritonavir, a potent CYP3A inhibitor, to enhance danoprevir pharmacokinetics. Ketoconazole is a substrate for and potent selective inhibitor of CYP3A. METHODS: In this open-label, 3-period study, the 2-way interaction potential between ritonavir-boosted danoprevir (danoprevir/r) and ketoconazole was investigated in 18 healthy subjects. Subjects initially received ketoconazole 200 mg q24h for 4 days (Period 1) followed by a 7-day washout period. Danoprevir/r 100/100 mg q12h was then given for 10 days (Period 2) followed by a further 4 days of danoprevir/r 100/100 mg q12h plus ketoconazole 200 mg q24h (Period 3). Serial blood samples were collected for the determination of danoprevir, ritonavir and/or ketoconazole plasma concentrations, and calculation of pharmacokinetic parameters. Safety and tolerability were monitored throughout the study. RESULTS: Co-administration of ketoconazole with danoprevir/r modestly increased the danoprevir AUCτ by 1.44-fold, with no effect on danoprevir Cmax. Co-administration of danoprevir/r with ketoconazole substantially increased ketoconazole AUCτ and Cmax by 3.71-fold and 1.73-fold, respectively. Danoprevir/r was well tolerated when administered alone or with ketoconazole. CONCLUSIONS: These results indicate that the effect of potent CYP3A inhibitors, such as ketoconazole, on danoprevir/r pharmacokinetics is not likely to be clinically relevant.
Subject(s)
Cytochrome P-450 CYP3A Inhibitors , HIV Protease Inhibitors/pharmacokinetics , Ketoconazole/pharmacology , Lactams/pharmacokinetics , Ritonavir/pharmacology , Sulfonamides/pharmacokinetics , Adult , Area Under Curve , Cyclopropanes , Drug Interactions , Female , Humans , Isoindoles , Lactams, Macrocyclic , Male , Middle Aged , Proline/analogs & derivativesABSTRACT
AIM: Pegylated interferon-based therapy is recommended for treatment of hepatitis C virus (HCV) infection. Because interferons are known to down-regulate hepatic cytochrome P450 (CYP) enzymes, which are involved in drug metabolism and clearance, there is a need to investigate the effect of peginterferon (PEG-IFN) alfa-2a (40KD) on the activity of these enzymes in vivo. METHODS: Fourteen healthy, male volunteers aged 18 to 45 years were recruited into an open label, two period, single centre study in which CYP enzyme activity was measured by administration of the selectively metabolized probe drugs theophylline (CYP1A2), tolbutamide (CYP2C9), mephenytoin (CYP2C19), debrisoquine (CYP2D6) and dapsone (CYP3A4) on day 1 of the study. PEG-IFN alfa-2a (40KD) 180 µg was given subcutaneously each week from day 15 to 36, and probe drugs were re-administered on day 37. Probe drugs and metabolites were quantified in plasma or urine samples and used to derive pharmacokinetic parameters. RESULTS: PEG-IFN alfa-2a (40KD) significantly increased the area under the serum drug concentration vs. time curve (AUC(0,∞)) for theophylline by 24%, with a reduction in the mean oral clearance of theophylline of 20%. There were no effects on the pharmacokinetics of any of the other probe drugs. The incidence of adverse events was as expected in subjects receiving pegylated interferon. CONCLUSION: These results suggest there may be an inhibitory effect of PEG-IFN alfa-2a (40KD) on CYP1A2. PEG-IFN alfa-2a (40KD) had no effect on CYP2C9, CYP2C19, CYP2D6 or CYP3A4 in healthy subjects.
Subject(s)
Cytochrome P-450 Enzyme System/metabolism , Interferon-alpha/pharmacology , Polyethylene Glycols/pharmacology , Adolescent , Adult , Antiviral Agents/pharmacology , Area Under Curve , Dose-Response Relationship, Drug , Drug Interactions , Humans , Male , Middle Aged , Recombinant Proteins/pharmacology , Young AdultABSTRACT
PURPOSE: The aim of this study was to evaluate the effects of danoprevir in combination with low-dose ritonavir (danoprevir/r) and placebo plus low-dose ritonavir on the pharmacokinetics of probe drugs for cytochrome P450 (CYP) 3A and CYP2C9, in patients with chronic hepatitis C. METHODS: A total of 54 patients infected with hepatitis C virus genotype 1 received an oral drug cocktail (2 mg midazolam, 10 mg warfarin and 10 mg vitamin K) before and after 14 days of dosing with either danoprevir/r or placebo plus low-dose ritonavir (placebo/r). Serial pharmacokinetic samples were collected up to 24 (midazolam) and 72 (S-warfarin) h post-dose. Plasma concentrations of midazolam, α-hydroxymidazolam and S-warfarin were measured using validated assays. Pharmacokinetic parameters were estimated using non-compartmental analysis, and geometric mean ratios (GMRs) and 90 % confidence intervals (CIs) for the differences between baseline and post-dosing values were calculated. RESULTS: Danoprevir/r and placebo/r significantly increased midazolam area under the time-concentration curve (AUC0-∞) and reduced the midazolam metabolic ratio while S-warfarin AUC0-∞ was modestly decreased. When danoprevir data were pooled across doses, the midazolam GMR (90 % CI) AUC0-∞ was 9.41 (8.11, 10.9) and 11.14 (9.42, 13.2) following danoprevir/r and placebo/r dosing, respectively, and the S-warfarin GMR (90 % CI) AUC0-∞ was 0.72 (0.68, 0.76) and 0.76 (0.69, 0.85), respectively. The effects of danoprevir/r and placebo/r appeared to be qualitatively similar. CONCLUSIONS: Substantial inhibition of CYP3A- and modest induction of CYP2C9- activity were observed with danoprevir/r and low-dose ritonavir.
Subject(s)
Antiviral Agents/administration & dosage , Hepatitis C, Chronic/metabolism , Lactams/administration & dosage , Midazolam/pharmacokinetics , Ritonavir/administration & dosage , Sulfonamides/administration & dosage , Warfarin/pharmacokinetics , Adult , Aryl Hydrocarbon Hydroxylases/metabolism , Cyclopropanes , Cytochrome P-450 CYP2C9 , Cytochrome P-450 CYP3A/metabolism , Drug Interactions , Drug Therapy, Combination , Female , Hepatitis C, Chronic/drug therapy , Humans , Isoindoles , Lactams, Macrocyclic , Male , Midazolam/administration & dosage , Midazolam/blood , Middle Aged , Proline/analogs & derivatives , Vitamin K/administration & dosage , Warfarin/administration & dosage , Warfarin/blood , Young AdultABSTRACT
PURPOSE: This phase Ib study defined the safety, MTD, and recommended phase II dose (RP2D) of regorafenib combined with vincristine and irinotecan (VI). Secondary objectives were evaluation of antitumor activity and pharmacokinetics (PK) of regorafenib and irinotecan. PATIENTS AND METHODS: Patients aged 6 months to <18 years with relapsed/refractory solid malignancies [≥50% with rhabdomyosarcoma (RMS)] received regorafenib (starting dose 72 mg/m2/day) concomitantly or sequentially with vincristine 1.5 mg/m2 on days 1 and 8, and irinotecan 50 mg/m2 on days 1-5 (21-day cycle). Adverse events (AE) and tumor response were assessed. PK (regorafenib and irinotecan) were evaluated using a population PK model. RESULTS: We enrolled 21 patients [median age, 10 years; 12, RMS; 5, Ewing sarcoma (EWS)]. The MTD/RP2D of regorafenib in the sequential schedule was 82 mg/m2. The concomitant dosing schedule was discontinued because of dose-limiting toxicities in 2 of 2 patients treated. Most common grade 3/4 (>30% of patients) AEs were neutropenia, anemia, thrombocytopenia, and leukopenia. The overall response rate was 48% and disease control rate [complete response (CR)/partial response/stable disease/non-CR/non-progressive disease] was 86%. Median progression-free survival was 7.0 months [95% confidence interval (CI), 2.9-14.8] and median overall survival was 8.7 months (95% CI, 5.5-16.3). When combined with VI, regorafenib PK was similar to single-agent PK in children and adults (treated with regorafenib 160 mg/day). CONCLUSIONS: Regorafenib can be combined sequentially with standard dose VI in pediatric patients with relapsed/refractory solid tumors with appropriate dose modifications. Clinical activity was observed in patients with RMS and EWS (ClinicalTrials.gov NCT02085148).
Subject(s)
Rhabdomyosarcoma , Sarcoma, Ewing , Adult , Child , Humans , Irinotecan , Vincristine , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Rhabdomyosarcoma/drug therapy , Sarcoma, Ewing/drug therapy , Therapies, InvestigationalABSTRACT
Background: Anti-programmed cell death protein 1 antibodies plus multikinase inhibitors have shown encouraging activity in several tumour types, including colorectal cancer. This study assessed regorafenib plus nivolumab in patients with microsatellite stable/mismatch repair-proficient metastatic colorectal cancer. Methods: This single-arm, open-label, multicentre phase 2 study enrolled adults from 13 sites in the USA with previously treated advanced microsatellite stable/mismatch repair-proficient metastatic colorectal cancer. Eligible patients had known extended RAS and BRAF status, progression or intolerance to no more than two (for extended RAS mutant) or three (for extended RAS wild type) lines of systemic chemotherapy and an Eastern Cooperative Oncology Group performance status of 0 or 1. Regorafenib 80 mg/day was administered orally for 3 weeks on/1 week off (increased to 120 mg/day if 80 mg/day was well tolerated) with intravenous nivolumab 480 mg every 4 weeks. Primary endpoint was objective response rate. Secondary endpoints included safety, overall survival, and progression-free survival. Exploratory endpoints included biomarkers associated with antitumour activity. Patients who received at least one dose of study intervention were included in the efficacy and safety analyses. Tumour assessments were carried out every 8 weeks for the first year, and every 12 weeks thereafter until progressive disease/end of the study, and objective response rate was analysed after all patients had met the criteria for primary completion of five post-baseline scans and either 10-months' follow-up or drop out. This trial is registered with ClinicalTrials.gov, number NCT04126733. Findings: Between 14 October 2019 and 14 January 2020, 94 patients were enrolled, 70 received treatment. Five patients had a partial response, yielding an objective response rate of 7% (95% CI 2.4-15.9; p = 0.27). All responders had no liver metastases at baseline. Median overall survival (data immature) and progression-free survival were 11.9 months (95% CI 7.0-not evaluable) and 1.8 months (95% CI 1.8-2.4), respectively. Most patients (97%, 68/70) experienced a treatment-related adverse event; 51% were grade 1 or 2, 40% were grade 3, 3% were grade 4, and 3% were grade 5. The most common (≥20%) events were fatigue (26/70), palmar-plantar erythrodysesthesia syndrome (19/70), maculopapular rash (17/70), increased blood bilirubin (14/70), and decreased appetite (14/70). Higher baseline expression of tumour biomarkers of immune sensitivity correlated with antitumour activity. Interpretation: Further studies are warranted to identify subgroups of patients with clinical characteristics or biomarkers that would benefit most from treatment with regorafenib plus nivolumab. Funding: Bayer/Bristol Myers Squibb.
ABSTRACT
There is an unmet need for an intravenous (i.v.) neuraminidase inhibitor, particularly for patients with severe influenza who cannot take oral medication. Two phase I pharmacokinetic and safety studies of i.v. oseltamivir were carried out in healthy volunteers. The first was an open-label, randomized, four-period, two-sequence, single-dose trial of 100 mg, 200 mg, and 400 mg oseltamivir i.v. over 2 h and a 75-mg oral dose of oseltamivir. The second was a double-blind, placebo-controlled, parallel-group, multiple-dose study in which participants were randomized to 100 mg or 200 mg oseltamivir or placebo (normal saline) i.v. over 2 h every 12 h for 5 days. Exposure to the active metabolite oseltamivir carboxylate (OC) after dosing achieved with 100 mg oseltamivir administered i.v. over 2 h was comparable to that achieved with 75 mg administered orally. Single i.v. doses of oseltamivir up to 400 mg were well tolerated with no new safety signals. Multiple-dose data confirmed good tolerability of 100 mg and 200 mg oseltamivir and showed efficacious OC exposures with 100 mg i.v. over 2 h twice daily for 5 days. These results support further exploration of i.v. oseltamivir as an influenza treatment option for patients unable to take oral medication.
Subject(s)
Antiviral Agents/pharmacokinetics , Enzyme Inhibitors/pharmacokinetics , Oseltamivir/analogs & derivatives , Oseltamivir/pharmacokinetics , Administration, Oral , Adolescent , Adult , Antiviral Agents/blood , Area Under Curve , Biological Availability , Dose-Response Relationship, Drug , Double-Blind Method , Drug Administration Schedule , Enzyme Inhibitors/blood , Female , Humans , Injections, Intravenous , Male , Middle Aged , Oseltamivir/blood , Oseltamivir/metabolism , PlacebosABSTRACT
Danoprevir, a potent, selective inhibitor of HCV NS3/4A protease, has a short half-life in humans. Therefore, the feasibility of a controlled release (CR) formulation to allow less frequent dosing was investigated using experimental approaches and physiological modeling to examine whether danoprevir is absorbed in the colon. Danoprevir absorption was studied in portal-vein-cannulated monkeys and in monkeys surgically modified to make intraduodenal, intrajejunal, intracolonic and oral administration possible. In portal-vein-cannulated monkeys, absorption was apparent up to 24 h after administration. The observed relative bioavailability from intracolonic delivery in the monkey was approximately 30% relative to oral administration, consistent with the model prediction of 40%. Human relative bioavailability for a tablet delivered to the colon compared with an immediate release (IR) formulation was predicted to be 4-28%. Preclinical data and modeling suggested that CR development would be challenging for this Biopharmaceutics Classification System Class IV compound. Therefore, a confirmative study in healthy volunteers was conducted to investigate the relative bioavailability of danoprevir in various regions of the gastrointestinal tract. In a randomized, open-label, crossover study, subjects received 100 mg danoprevir IR soft gel capsule, 100 mg danoprevir solution delivered to the distal small bowel and colon via an Enterion™ capsule (a remotely activated capsule for regional drug delivery) and 100 mg danoprevir powder to the colon via an Enterion™ capsule. The relative bioavailability of danoprevir (compared with IR) delivered to the colon was 6.5% for a solution and 0.6% for a powder formulation, indicating that a CR formulation is not feasible.
Subject(s)
Antiviral Agents/pharmacokinetics , Intestinal Absorption , Lactams/pharmacokinetics , Models, Biological , Sulfonamides/pharmacokinetics , Administration, Oral , Adult , Animals , Antiviral Agents/administration & dosage , Biological Availability , Cross-Over Studies , Cyclopropanes , Delayed-Action Preparations , Feasibility Studies , Humans , Isoindoles , Lactams/administration & dosage , Lactams, Macrocyclic , Macaca fascicularis , Male , Proline/analogs & derivatives , Sulfonamides/administration & dosage , Young AdultABSTRACT
PURPOSE: To assess the translational value of anticancer preclinical models, we retrospectively investigated the relationships between preclinical data and clinical response rate for 42 small-molecule targeted anticancer drugs approved by the US FDA from 2001 to 2018. METHODS: For 42 FDA-approved drugs, relevant pre-clinical (IC50, mouse PK/efficacy) and clinical (overall response rates [ORR], PK) data were extracted from the public domain. Relationships were investigated overall and separately by mechanism of action and solid vs liquid tumors. Binomial-normal regression analysis was performed using R. RESULTS: A significant correlation was found between the ratio of free human average plasma concentration (hCave) at the approved clinical dose to biochemical IC50 and ORR for kinase inhibitors with solid tumor indications (KIST). We also identified that, for KIST, the ratios of (i) total and (ii) free human-to-mouse average plasma concentration at efficacious doses were correlated to ORR ((i) R2 = 0.72, n = 10; (ii) R2 = 0.78, n = 10)). CONCLUSION: Relationships were identified for ratios of efficacious clinical exposures to typical preclinical pharmacology data and ORR for KIST in this retrospective analysis. Although the obtained datasets are limited, the relationships demonstrate that a systemic exposure relative to established pre-clinical pharmacology experiments for an investigational KIST could be used as a reference to assess if desired efficacy could be achieved. This approach may assist selection of the recommended phase 2 dose (RP2D) of an investigational drug.
Subject(s)
Antineoplastic Agents/therapeutic use , Drug Approval , Drugs, Investigational/therapeutic use , Neoplasms/drug therapy , Protein Kinase Inhibitors/therapeutic use , Small Molecule Libraries/therapeutic use , Animals , Humans , Mice , Neoplasms/pathology , United States , United States Food and Drug AdministrationABSTRACT
BACKGROUND: Viral kinetic models have proven useful in characterizing treatment effectiveness during HCV therapy with interferon (IFN) as well as with direct-acting antivirals (DAAs). METHODS: Here we use a pharmacokinetic/viral kinetic (PK/VK) model to describe HCV RNA kinetics during treatment with setrobuvir, a non-nucleosidic inhibitor of the HCV NS5B polymerase enzyme. Using PK data from three studies in healthy volunteers and PK and VK data from a Phase I study, where setrobuvir was administered for 3 days, we fitted a two-compartment PK model with first-order absorption and lag-time, an Emax pharmacodynamics model and a standard biphasic VK model. RESULTS: Setrobuvir's EC50 and Hill coefficient and the viral clearance rate were significantly different (P=0.014, P<0.001 and P=0.004, respectively) between patients infected with HCV subtypes 1b and 1a, leading to an increased viral load decline in patients infected with genotype 1b virus. CONCLUSIONS: Understanding the combined effects of PK/VK on the performance of a non-nucleoside polymerase inhibitor such as setrobuvir could provide valuable insights into their use in combination with other DAAs as well as to optimize future therapy. Further, our work suggests that patients infected with subtype 1a would need higher doses than those infected with subtype 1b to achieve the same effectiveness. Whether this is true for other non-nucleoside polymerase inhibitors needs to be examined.
Subject(s)
Antiviral Agents/therapeutic use , Hepacivirus/drug effects , Hepatitis C, Chronic/drug therapy , Hepatitis C, Chronic/virology , Viral Load/drug effects , Algorithms , Antiviral Agents/pharmacokinetics , Drug Therapy, Combination , Female , Genotype , Humans , Male , Models, Theoretical , RNA, Viral , Treatment OutcomeABSTRACT
The purpose of this study was to investigate the potential for a CYP3A4-mediated drug interaction between R667 and midazolam (MDZ) in healthy subjects. R667 is metabolized by CYP3A4 and therefore may interact with CYP3A4 substrates. In the present study, 18 healthy male subjects received a single 15-mg oral dose of MDZ with and without R667 coadministration. Serial blood samples were collected predose and up to 24 hours after each MDZ dose for pharmacokinetic (PK) evaluation. The PK parameters for MDZ, R667, and metabolites were estimated using noncompartmental methods. MDZ exposure was very similar in the presence and absence of R667 (C(max) = 50.8 vs 46.2 ng/mL; AUC(0-last) = 215 vs 216 ng.h/mL; AUC(0-last) ratio = 0.26 vs 0.26, respectively). R667 exposure was not affected by midazolam coadministration as compared with historical data. Based on the results of this study, no significant pharmacokinetic interaction should be anticipated between R667 and CYP3A4 substrates.
Subject(s)
Emphysema/drug therapy , Hypnotics and Sedatives/pharmacokinetics , Midazolam/pharmacokinetics , Adult , Area Under Curve , Biotransformation , Cross-Over Studies , Cytochrome P-450 CYP3A , Cytochrome P-450 Enzyme System/metabolism , Half-Life , Humans , Male , Midazolam/analogs & derivatives , Midazolam/blood , Pyrazoles/adverse effects , Pyrazoles/pharmacologyABSTRACT
BACKGROUND AND AIM: Effective and safe antiviral treatment regimens are needed for patients with chronic hepatitis C (CHC) and cirrhosis. METHODS: An international open-label trial was conducted in CHC patients with genotype (G)1/4 infection, compensated cirrhosis, HCV RNA ≥ 50,000 IU/mL and body mass index 18-35 kg/m(2). Treatment-naive patients (Cohort 1) received a triple therapy regimen [danoprevir/r 100/100 mg twice daily (bid), ribavirin 1000/1200 mg/day and peginterferon alfa-2a 180 µg/week] for 24 weeks. Prior null responders (Cohort 2) received a quadruple therapy regimen (danoprevir/r 100/100 mg bid, mericitabine 1000 mg bid and peginterferon alfa-2a/ribavirin). The primary efficacy outcome was sustained virological response (HCV RNA < limit of quantification, target not detected) at end of the 24-week follow-up period (SVR24). RESULTS: In Cohort 1 (n = 23), 73.9 and 65.2 % of patients had a virological response at Weeks 4 and 24, respectively; 39.1 % achieved SVR24 (G1a = 1/13; G1b = 8/9; G4 = 0/1). In Cohort 2 (n = 20), 100 % achieved virological response at Weeks 4 and 24; 65 % achieved SVR24 (G1a = 4/8; G1b = 7/10; G4 = 2/2). Treatment failure was more common in G1a than G1b-infected patients and less common in patients receiving quadruple therapy. Treatment failure was associated with emergence of resistance to danoprevir, but not mericitabine. The safety profile was typical of that associated with peginterferon alfa-2a/ribavirin. No deaths/episodes of hepatic decompensation occurred. CONCLUSIONS: Treatment with danoprevir/r-based regimens for 24 weeks is safe and well tolerated in CHC patients with compensated cirrhosis. A quadruple therapy regimen (danoprevir/r, mericitabine, peginterferon alfa/ribavirin) produced high SVR24 rates in prior null responders, particularly among G1b patients.
Subject(s)
Antiviral Agents/therapeutic use , Hepacivirus/drug effects , Hepatitis C/drug therapy , Lactams/therapeutic use , Liver Cirrhosis/etiology , Ritonavir/therapeutic use , Sulfonamides/therapeutic use , Antiviral Agents/administration & dosage , Cyclopropanes , Drug Administration Schedule , Female , Hepacivirus/genetics , Hepatitis C/complications , Hepatitis C/virology , Humans , Interferon-alpha/administration & dosage , Interferon-alpha/therapeutic use , Isoindoles , Lactams/administration & dosage , Lactams, Macrocyclic , Liver Cirrhosis/virology , Male , Middle Aged , Polyethylene Glycols/administration & dosage , Polyethylene Glycols/therapeutic use , Proline/analogs & derivatives , Recombinant Proteins/administration & dosage , Recombinant Proteins/therapeutic use , Ribavirin/administration & dosage , Ribavirin/therapeutic use , Ritonavir/administration & dosage , Sulfonamides/administration & dosage , Treatment FailureABSTRACT
Availability of lower-dose oseltamivir capsules, an increased pharmacokinetic database, and a desire to align drug exposure across the spectrum of renal function prompted reassessment of oral dosing in patients with renal impairment. The data set comprised 128 subjects (71 with varying degrees of renal impairment) from 8 studies, which included single and multiple doses of 20-1000 mg. Pharmacokinetic profiles of oseltamivir phosphate (OP) and oseltamivir carboxylate (OC) were modeled simultaneously in NONMEM. Exposure metrics of OP and OC (AUC48 h , Cmax , Cmin ) after administration of various dosing regimens were simulated for renal impairment subgroups and compared with exposures in patients with normal renal function receiving approved regimens. For influenza treatment, 30 mg once-daily and twice-daily regimens were selected for severe and moderate impairment, respectively. These regimens provided OC exposures similar or above those of the approved 75-mg twice-daily treatment regimen in subjects with normal renal function. For influenza prophylaxis, 30 mg once every other day and once-daily regimens were selected for severe and moderate impairment, respectively. No dosing adjustments were required for mild impairment. This analysis supported revised labeling in the United States and Europe for oral oseltamivir dosing in patients with moderate and severe renal impairment.
Subject(s)
Glycoside Hydrolase Inhibitors/administration & dosage , Glycoside Hydrolase Inhibitors/pharmacokinetics , Influenza, Human/drug therapy , Kidney Diseases/physiopathology , Kidney/physiopathology , Neuraminidase/antagonists & inhibitors , Oseltamivir/analogs & derivatives , Administration, Oral , Adolescent , Adult , Aged , Area Under Curve , Computer Simulation , Drug Administration Schedule , Female , Glycoside Hydrolase Inhibitors/adverse effects , Glycoside Hydrolase Inhibitors/blood , Humans , Influenza, Human/blood , Influenza, Human/virology , Kidney/metabolism , Kidney Diseases/blood , Kidney Diseases/diagnosis , Male , Metabolic Clearance Rate , Middle Aged , Models, Biological , Neuraminidase/metabolism , Nonlinear Dynamics , Oseltamivir/administration & dosage , Oseltamivir/adverse effects , Oseltamivir/blood , Oseltamivir/pharmacokinetics , Randomized Controlled Trials as Topic , Severity of Illness Index , Young AdultABSTRACT
BACKGROUND AND OBJECTIVES: Understanding transmembrane transport provides a more complete understanding of the pharmacokinetics of a drug and mechanistic explanations for drug-drug interactions. Here, the transmembrane transport of danoprevir (hepatitis C virus protease inhibitor) and the effects of ritonavir and ciclosporin on transmembrane transport of danoprevir were evaluated and clinical pharmacokinetic studies of danoprevir co-administered with/without ritonavir and ciclosporin were conducted. METHODS: Transcellular transport of danoprevir was evaluated in Lewis lung cancer porcine kidney, Madin-Darby canine kidney, or Chinese hamster ovary cells transfected with human transport proteins, and in human hepatocytes. The pharmacokinetics of intravenous and oral danoprevir administered with/without ritonavir, and the impact of ciclosporin on danoprevir pharmacokinetics were evaluated in randomized, open-label, crossover studies in healthy subjects. RESULTS: Danoprevir transport in vitro involved organic anion transporting polypeptide (OATP) 1B1, OATP1B3, P-glycoprotein, and multidrug resistance protein-2, but not breast cancer resistance protein. Ritonavir and ciclosporin inhibited transport of danoprevir by human hepatocytes. The pharmacokinetics of intravenous danoprevir 6 mg were not altered by oral ritonavir 100 mg. In contrast, exposure to oral danoprevir 100 mg increased two- to threefold when co-administered with ritonavir. Absolute bioavailability of danoprevir 100 mg was low (1.15%), but increased more than threefold (3.86%) when co-administered with ritonavir. Oral ciclosporin 100 mg increased exposure to intravenous danoprevir 2 mg and oral ritonavir 100 mg. CONCLUSION: Collectively, these studies provide insight into the transmembrane transport and pharmacokinetics of danoprevir and the mechanisms that underlie a recently reported, three-way drug-drug interaction involving danoprevir, ritonavir, and ciclosporin.
Subject(s)
Lactams/pharmacokinetics , Membrane Transport Proteins/metabolism , Protease Inhibitors/pharmacokinetics , Sulfonamides/pharmacokinetics , Adolescent , Adult , Animals , Antiviral Agents/pharmacokinetics , Antiviral Agents/pharmacology , Biological Availability , CHO Cells , Carcinoma, Lewis Lung/metabolism , Cricetinae , Cricetulus , Cross-Over Studies , Cyclopropanes , Cyclosporine/pharmacology , Dogs , Drug Interactions , Female , Hepatocytes/metabolism , Humans , Isoindoles , Lactams/pharmacology , Lactams, Macrocyclic , Madin Darby Canine Kidney Cells , Male , Middle Aged , Proline/analogs & derivatives , Protease Inhibitors/pharmacology , Randomized Controlled Trials as Topic , Ritonavir/pharmacology , Sulfonamides/pharmacology , Swine , Young AdultABSTRACT
STUDY OBJECTIVE: To investigate the steady-state pharmacokinetics of methadone when coadministered with ritonavir-boosted danoprevir (DNVr). DESIGN: Open-label, two-period, single-sequence pharmacokinetic study. SETTING: Two U.S. research centers. PATIENTS: Eighteen methadone-maintained healthy adults. MEASUREMENTS AND MAIN RESULTS: In Period 1 (Day -1), subjects received their daily methadone maintenance therapy (MMT). In Period 2 (Days 1-10), subjects received MMT plus DNVr 100/100 mg twice/day. Pharmacokinetic parameters for the total concentrations of (R)- and (S)-methadone on Days -1 and 10 were determined using noncompartmental methods. Unbound (R)- and (S)-methadone concentrations at 3 hours postdose were also assessed on Days -1 and 10. Geometric mean ratios (GMRs) and 90% confidence intervals (CIs) were used to compare steady-state (R)- and (S)-methadone pharmacokinetics when MMT was administered with or without DNVr. Methadone withdrawal was assessed using the Subjective Opiate Withdrawal Scale. Compared with MMT alone, methadone AUCtau and Cmax GMR (90% CI) following coadministration with DNVr were 1.02 (0.91-1.15) and 1.01 (0.90-1.13) for (R)-methadone, and 1.01 (0.90-1.13) and 0.99 (0.89-1.10) for (S)-methadone, respectively. Unbound (R- and (S)-methadone concentrations were comparable with or without DNVr. No instances of methadone withdrawal were reported. MMT in combination with DNVr was well tolerated. CONCLUSION: Coadministration of DNVr with MMT resulted in no significant pharmacokinetic interactions or signs of methadone withdrawal. No dosage adjustment is needed for MMT when coadministered with DNVr.
Subject(s)
Drug Interactions , Lactams/pharmacokinetics , Methadone/pharmacokinetics , Opiate Substitution Treatment/methods , Protease Inhibitors/pharmacokinetics , Ritonavir/pharmacokinetics , Sulfonamides/pharmacokinetics , Adolescent , Adult , Aged , Cyclopropanes , Drug Interactions/physiology , Drug Therapy, Combination , Humans , Isoindoles , Lactams/administration & dosage , Lactams, Macrocyclic , Methadone/administration & dosage , Middle Aged , Proline/analogs & derivatives , Protease Inhibitors/administration & dosage , Ritonavir/administration & dosage , Sulfonamides/administration & dosage , Young AdultABSTRACT
OBJECTIVES: To evaluate the effect of a low- and high-fat meal and co-administration of ranitidine or omeprazole on the pharmacokinetics of ritonavir-boosted danoprevir (DNVr). METHODS: In this randomised, open-label, cross-over study, healthy subjects received a single dose of DNVr. In group 1, DNVr was administered while fasting or with a low-fat or high-fat meal. In group 2, DNVr was administered alone or with ranitidine 150 mg (single dose) or omeprazole 40 mg (multiple doses). KEY FINDINGS: Group 1 (n = 16): relative to fasting conditions, food slightly prolonged absorption but did not alter the extent of absorption. DNV area under the plasma concentration-time curve extrapolated to infinity (AUC0-∞), maximum plasma concentration (C(max)), and plasma concentration 12 h after administration (C12h) geometric mean ratios (GMR%) (90% confidence interval (CI)) with a low-fat meal were 92.3 (80.2-106), 61.8 (51.0-74.9) and 95.2 (80.9-112), versus fasting conditions, and with a high-fat meal 99.5 (86.4-115), 58.9 (48.5-71.6) and 101 (86.0-119). Group 2 (n = 13): ranitidine or omeprazole had no clinically significant effect on DNV pharmacokinetics. DNV AUC0-∞, Cmax and C12h GMR% (90% CI) with ranitidine: 81.9 (68.3-98.1), 104 (86.9-123) and 87.5 (69.3-111), and with omeprazole: 83.0 (67.4-102), 92.7 (70.6-122) and 93.3 (65.6-133). CONCLUSIONS: The absence of clinically relevant effects of food, ranitidine or omeprazole on DNVr pharmacokinetics suggests that DNVr can be administered without regard to meals and in combination with H2 antagonists or proton pump inhibitors.