Population Pharmacokinetics of the Novel Adenosine A2A Antagonist/Inverse Agonist KW-6356 and Its Active Metabolite Following Single and Multiple Oral Administration in Healthy Individuals and Patients with Parkinson's Disease.

KW-6356 is a selective antagonist and inverse agonist of the adenosine A2A receptor. The primary aim of the present analysis was to characterize the pharmacokinetics (PK) of KW-6356 and its active metabolite M6 in healthy subjects and patients with Parkinson's disease (PD). We pooled concentration-time data from healthy subjects and patients with PD who were administered KW-6356. Using these data, we developed a population PK model by sequentially fitting the KW-6356 parameters followed by the M6 parameters. A first-order absorption with a 1-compartment model for KW-6356 and a 1-compartment model for M6 best described the profiles. The covariates included in the final models were food status (fed/fasted/unknown) on first-order absorption rate constant, baseline serum albumin level on apparent clearance of KW-6356, and baseline body weight on apparent volume of distribution of KW-6356 and apparent clearance of M6. No covariate had a clinically meaningful impact on KW-6356 or M6 exposure.

Population pharmacokinetics analysis of nivolumab in Asian and non-Asian patients with gastric and gastro-esophageal junction cancers.

PURPOSE: Nivolumab monotherapy provided clinically meaningful antitumor activity in Asian and non-Asian patients with chemotherapy-refractory gastric cancer (GC) or gastro-esophageal junction cancer (GEJC) in the ATTRACTION-2 and CheckMate 032 studies, respectively. This analysis assessed the population pharmacokinetics (PopPK) of nivolumab, the impact of covariates on pharmacokinetics (PK), and the PK of nivolumab flat dosing in GC/GEJC using samples from these studies. METHODS: PopPK analyses were conducted using data from 1302 patients with solid tumors, including 387 patients with GC/GEJC who had received nivolumab 3 mg/kg once every 2 weeks (Q2W). The impact of covariates on nivolumab PK was assessed in the full model. Nivolumab exposures following a flat dose of 240 mg Q2W in patients with GC/GEJC were simulated and compared with those of 3 mg/kg Q2W. RESULTS: Nivolumab PK was described using a 2-compartment, zero-order intravenous infusion and time-varying clearance (CL) model. Baseline CL in patients with GC/GEJC was ~ 33% greater than in patients with non-small cell lung cancer (NSCLC) in second line or subsequent lines of treatment (2L+). The effect of race was not clinically relevant (< 20% difference). Nivolumab exposures following 240 mg Q2W were similar to 3 mg/kg Q2W in non-Asian patients and 46% higher in Asian patients due to lower body weight. CONCLUSIONS: Nivolumab CL was increased in GC/GEJC relative to NSCLC 2L+. Higher nivolumab exposures achieved with 240 mg Q2W in Asian patients are predicted to be below the acceptable safety margin, supporting the use of a flat dose in both patient populations.

Population Pharmacokinetics and Exposure - Safety Analyses of Nivolumab in Patients With Relapsed or Refractory Classical Hodgkin Lymphoma.

Nivolumab, a fully human immunoglobulin G4 monoclonal anti-programmed death-1 antibody, has demonstrated clinical benefits in multiple tumors, including classical Hodgkin lymphoma. The aim of this study was to characterize the pharmacokinetics (PK) of nivolumab in patients with classical Hodgkin lymphoma using a population approach and to assess the exposure-response (E-R) relationship for safety, thereby supporting the dose recommendation in patients with classical Hodgkin lymphoma. Nivolumab PK and the effect of covariates were consistent with that observed in solid tumors, except that baseline clearance of nivolumab was lower in patients with classical Hodgkin lymphoma by 28%. The E-R analysis for safety, characterized by a Cox proportional hazards model, indicated that the resulting increased nivolumab exposure (average concentration after the first dose) was not a significant predictor of the risk of grade ≥3 drug-related adverse events. Given the acceptable safety profile and observed benefit (65% objective response rate) with the nivolumab 3 mg/kg every 2 week dosing regimen for classical Hodgkin lymphoma, together with the flat E-R safety relationship, nivolumab demonstrated a favorable benefit-risk profile across the range of exposures of 3 mg/kg every 2 weeks in patients with classical Hodgkin lymphoma. Additional model-based simulation suggested that a flat dose of 240 mg every 2 weeks was predicted to produce similar exposures to that of 3 mg/kg every 2 weeks. Therefore, nivolumab 240 mg every 2 weeks is the recommended dosing regimen in the classical Hodgkin lymphoma population.

CYP2C19 Genotype-Dependent Pharmacokinetic Drug Interaction Between Voriconazole and Ritonavir-Boosted Atazanavir in Healthy Subjects.

Voriconazole, a broad-spectrum triazole antifungal agent, is metabolized by cytochrome P450 (CYP) 2C19 and, to a lesser extent, by CYP3A. Genetic polymorphism of CYP2C19 not only plays a prominent role in its disposition but may also influence potential drug interactions with CYP450 modulators such as ritonavir. This study assessed 2-way drug interactions of voriconazole added on to ritonavir-boosted atazanavir in both CYP2C19 extensive-metabolizer (EM) and poor-metabolizer (PM) healthy subjects. Each subject received voriconazole alone on days 1-3, followed by a 7-day washout. Atazanavir/ritonavir 300/100 mg once daily was given on days 11-30 and voriconazole on days 21-30. Voriconazole doses were 200 mg (400 mg on days 1 and 21) twice daily and 50 mg (100 mg on days 1 and 21) twice daily for CYP2C19 EM and PM subjects, respectively. On coadministration, voriconazole AUC and Cmin decreased by 33% (90%CI, 22%-42%) and 39% (90%CI, 28%-49%), respectively, in CYP2C19 EMs, whereas voriconazole Cmax and AUC increased 4.4-fold (90%CI, 3.6-fold to 5.4-fold) and 5.6-fold (90%CI, 4.5-fold to 7.0-fold), respectively, in PMs. Adding voriconazole resulted in a 20%-30% decrease in atazanavir Cmin in both EMs and PMs. Ritonavir exposure was generally unchanged in either population. The safety and tolerability profiles of the combination were comparable with atazanavir/ritonavir and voriconazole administered alone. The most frequent adverse events with voriconazole were visual disturbance and headache. Coadministration of voriconazole and atazanavir/ritonavir is not recommended unless the benefit/risk to the patient justifies the use of the combination.

Mechanisms of Hyperbilirubinemia During Peginterferon Lambda-1a Therapy for Chronic Hepatitis C Infection: A Retrospective Investigation.

The phase 2b EMERGE study compared the efficacy/safety of peginterferon lambda-1a (Lambda) and peginterferon alfa-2a (Alfa), both with ribavirin (RBV), for treatment of chronic hepatitis C virus (HCV) infection. A key safety finding was a higher frequency of hyperbilirubinemia with Lambda/RBV versus Alfa/RBV. To characterize mechanisms of hyperbilirubinemia associated with Lambda/RBV, we conducted a retrospective analysis of safety data from the HCV genotype 1 and genotype 4 cohort of the EMERGE study. Subjects were randomized to once-weekly Lambda (120/180/240 µg) or Alfa (180 µg), with daily RBV, for 48 weeks. Early-onset Lambda/RBV-related hyperbilirubinemia events (6-12 weeks) resulted mostly from RBV-induced hemolysis evidenced by sustained reticulocytosis and a predominantly unconjugated pattern of hyperbilirubinemia. The higher hyperbilirubinemia frequency with Lambda/RBV versus Alfa/RBV was attributed to bone marrow suppression known to occur with Alfa but not Lambda. Late-onset (>12 weeks) Lambda/RBV-related hyperbilirubinemia events occurred most frequently with higher Lambda doses and were associated with increased levels of hepatic transaminase and direct bilirubin fractions compared with early events. This dual pattern of hyperbilirubinemia observed while on Lambda/RBV treatment is thought to be caused by exaggerated RBV-induced hemolysis in early-onset events compared with possible direct Lambda-induced hepatocellular toxicity in late-onset events.

Anti-PEG antibody bioanalysis: a clinical case study with PEG-IFN-λ-1a and PEG-IFN-α2a in naive patients.

BACKGROUND: Extensive use of polyethylene glycol (PEG) in consumer products necessitates the assessment of anti-PEG antibodies (APAb). METHODS: In clinical trials comparing PEG-IFN-λ to PEG-IFN-α, conventional bridge and direct assays were assessed. RESULTS & CONCLUSION: The bridge assay detected IgM and IgG APAb reactive with common PEG sizes and derivatives at sufficient sensitivity, 15-500 ng/ml. Of subjects evaluated, 6% of PEG-IFN-λ and 9% of PEG-IFN-α subjects had persistent APAb while 60% of PEG-IFN-λ and 33% of PEG-IFN-α subjects had persistent anti-interferon antibodies (AIAb). Pre-existing APAb and AIAb prevalence was comparable (approximately 10% of subjects). APAb were earlier onset, less frequent, less persistent and lower titer than AIAb. No associated hypersensitivity events were reported.

The pharmacokinetics of peginterferon lambda-1a following single dose administration to subjects with impaired renal function.

AIMS: This open label study was conducted to assess the effect of renal impairment (RI) on the pharmacokinetics (PK) of peginterferon lambda-1a (Lambda). METHODS: Subjects (age 18-75 years, BMI 18-35 kg m(-2) ) were enrolled into one of five renal function groups: normal (n = 12), mild RI (n = 8), moderate RI (n = 8), severe RI (n = 7), end-stage renal disease (ESRD, n = 8) based on estimated glomerular filtration rate (eGFR) calculated using the Modification of Diet in Renal Disease (MDRD) equation. Subjects received a single dose of Lambda (180 µg) subcutaneously on day 1 followed by PK serum sample collections through day 29. Safety, tolerability and immunogenicity data were collected through day 43. PK parameters were estimated and summarized by group. Geometric mean ratios (GMR) and 90% confidence intervals (CIs) were calculated between normal and RI groups. RESULTS: With decreasing eGFR, Lambda exposure (Cmax , AUC) increased while apparent clearance (CL/F) and apparent volume of distribution (V/F) decreased. Relative to subjects with normal renal function (geometric mean AUC = 99.5 ng ml(-1) h), Lambda exposure estimates (AUC) were slightly increased in the mild RI group (geometric mean [90% CI]: 1.20 [0.82, 1.77]) and greater in the moderate (1.95 [1.35, 2.83]), severe RI (1.95 [1.30, 2.93]) and ESRD (1.88 [1.30, 2.73]) groups. Lambda was generally well tolerated. CONCLUSIONS: The results demonstrated that RI reduces the clearance of Lambda and suggests that dose modifications may not be required in patients with mild RI but may be required in patients with moderate to severe RI or ESRD.

Effect of St John's wort on imatinib mesylate pharmacokinetics.

OBJECTIVE: Imatinib is a potent inhibitor of the Bcr-Abl and c- kit tyrosine kinases and is approved for the treatment of Philadelphia chromosome-positive chronic myelogenous leukemia and gastrointestinal stromal tumors. Because imatinib is predominantly metabolized by cytochrome P450 (CYP) 3A4, its pharmacokinetics may be altered when it is coadministered with drugs or herbs (eg, St John's wort) that modulate CYP3A4 activity. Thus we examined the effects of St John's wort on imatinib pharmacokinetics. METHODS: This 2-period, open-label, fixed-sequence study was completed by 12 healthy subjects (6 men and 6 women) aged between 20 and 51 years. Each subject received 400 mg imatinib orally on study day 1, St John's wort (300 mg 3 times daily) on days 4 to 17, and 400 mg imatinib again on day 15. Serial blood samples were obtained over a 72-hour period after each imatinib dose. Imatinib and N -desmethyl-imatinib (CGP 74588) were quantified in plasma by liquid chromatography-mass spectrometry. RESULTS: St John's wort administration increased imatinib clearance by 43% ( P < .001), from 12.5 +/- 3.6 L/h to 17.9 +/- 5.6 L/h; imatinib area under the concentration versus time curve (AUC) extrapolated to infinity was decreased by 30%, from 34.5 +/- 9.5 microg . h/mL to 24.2 +/- 7.0 microg . h/mL ( P < .001). Imatinib half-life (12.8 hours versus 9.0 hours) and maximum concentration (C max ) (2.2 microg/mL versus 1.8 microg/mL) were also significantly decreased ( P < .005). N -desmethyl-imatinib C max was increased from 285 +/- 95 ng/mL to 318 +/- 95 ng/mL during St John's wort dosing, but the AUC from 0 to 72 hours was not altered. CONCLUSIONS: These data indicate that St John's wort increases imatinib clearance. Thus patients taking imatinib should avoid taking St John's wort. Concomitant use of enzyme inducers, including St John's wort, may necessitate an increase in the imatinib dose to maintain clinical effectiveness.

Determination of trimethoprim in low-volume human plasma by liquid chromatography.

Trimethoprim is an anti-infective agent used in the treatment of urinary and respiratory tract infections and mild to moderate pneumocystis carinii pneumonia. Trimethoprim is also a selective in vitro inhibitor of cytochrome P450 2C8 and may have utility as an in vivo inhibitor of this enzyme. A simplified high performance liquid chromatography (HPLC) method was developed to determine trimethoprim in human plasma. Samples are processed by protein precipitation with perchloric acid and chromatographic separation is achieved on a Synergi Polar-RP column (4 micron, 150 mm x 4.6 mm) using a mobile phase consisting of 50 mM ammonium formate-acetonitrile-methanol (pH=3.0; 90:6:4 (v/v/v)). Detection is monitored at 280 nm. Intra- and inter-day precision ranged from 1.1 to 1.9 and 0.9 to 4.1%, respectively. The assay is simple, economical, precise, and is directly applicable to human studies involving steady state trimethoprim pharmacokinetics.

Simplified method for determination of rosiglitazone in human plasma.

Rosiglitazone is a thiazolidinedione antihyperglycemic drug used in the treatment of type 2 diabetes mellitus. Rosiglitazone is extensively metabolized by cytochrome P450 2C8 and so may have some utility as an in vivo probe for this enzyme. A liquid chromatographic method using sensitive fluorescence detection and simplified sample processing involving protein precipitation with acetonitrile was developed. The isocratic mobile phase consisted of 10 mM sodium acetate-acetonitrile (pH 5; 60:40, v/v) and was delivered at a flow rate of 1 ml/min to an Alltima phenyl column (250 mm x 4.6 mm, 5 microm). Detection was by fluorescence at (EX/EM) 247/367 for rosiglitazone and 235/310 for the internal standard betaxolol. Intra- and inter-day precision ranged from 3.1 to 8.5% and 2.3 to 5.7%, respectively. No endogenous interference was observed with either rosiglitazone or the internal standard. The assay is simple, economical, precise, and is directly applicable to human pharmacokinetic studies involving single dose rosiglitazone administration.