Avelumab Plus Talazoparib in Patients With Advanced Solid Tumors: The JAVELIN PARP Medley Nonrandomized Controlled Trial.

Importance: Preclinical data suggest that poly(ADP-ribose) polymerase (PARP) inhibitors have synergistic activity when combined with immune checkpoint inhibitors (ICIs); however, it is unknown which tumor types or molecular subtypes may benefit from this combination. Objective: To investigate responses associated with the combination of avelumab and talazoparib in different tumor types and/or molecular subtypes. Design, Setting, and Participants: In this phase 1b and 2 basket nonrandomized controlled trial, patients with advanced solid tumors were enrolled in the following cohorts: non-small cell lung cancer (NSCLC); DNA damage response (DDR)-positive NSCLC; triple-negative breast cancer (TNBC); hormone receptor-positive, human epidermal growth factor receptor 2 (ERBB2)-negative, DDR-positive breast cancer; recurrent, platinum-sensitive ovarian cancer (OC); recurrent, platinum-sensitive, BRCA1/2-altered OC; urothelial cancer; metastatic castration-resistant prostate cancer (mCRPC); DDR-positive mCRPC; and BRCA1/2- or ATM-altered solid tumors. Data were analyzed between June 17, 2021, and August 6, 2021. Interventions: All patients in phases 1b and 2 received avelumab plus talazoparib. Main Outcomes and Measures: The phase 1b primary end point was dose-limiting toxic effects. The phase 2 primary end point was objective response, measured as objective response rate (ORR). Secondary end points included safety, time to response, duration of response (DOR), progression-free survival, time to prostate-specific antigen progression and PSA response of 50% or greater (for mCRPC), cancer antigen 125 response (for OC), pharmacokinetics, immunogenicity, and biomarkers. Results: A total of 223 patients (mean [SD] age, 63.2 [11.0] years; 117 [52.5%] men) were treated, including 12 patients in phase 1b and 211 patients in phase 2. The recommended phase 2 dose was avelumab 800 mg every 2 weeks plus talazoparib 1 mg once daily. In phase 2, the ORR was 18.2% (95% CI, 5.2%-40.3%) in patients with TNBC; 34.8% (95% CI, 16.4%-57.3%) in patients with HR-positive, ERBB2-negative, and DDR-positive BC; and 63.6% (95% CI, 30.8%-89.1%) in patients with platinum-sensitive, BRCA1/2-altered OC. Responses occurred more frequently in patients with BRCA1/2-altered tumors. Durable responses were observed in patients with TNBC (median [range] DOR, 11.1 [3.4-20.4] months); HR-positive, ERBB2-negative, and DDR-positive BC (median [range] DOR, 15.7 [3.9 to ≥20.6] months); and BRCA1/2-altered OC (median DOR not reached; range, 5.6 to ≥18.4 months). The most common grade 3 or greater treatment-related adverse events were anemia (75 patients [33.6%]), thrombocytopenia (48 patients [21.5%]), and neutropenia (31 patients [13.9%]). Conclusions and Relevance: This nonrandomized controlled trial found that ORRs for avelumab plus talazoparib were comparable with those with PARP inhibitor or ICI monotherapy. Prolonged DOR in patients with TNBC; HR-positive, ERBB2-negative, and DDR-positive BC; and BRCA1/2-altered OC warrant further investigation in randomized clinical trials. These data highlight the importance of prospective patient selection in future studies of ICI and PARP-inhibitor combinations. Trial Registration: ClinicalTrials.gov Identifier: NCT03330405.

Radiation Dosimetry of Theragnostic Pairs for Isotopes of Iodine in IAZA.

Theragnostic pairs of isotopes are used to infer radiation dosimetry for a therapeutic radiopharmaceutical from a diagnostic imaging study with the same tracer molecule labelled with an isotope better suited for the imaging task. We describe the transfer of radiation dosimetry from the diagnostic radioiodine isotope 123I, labelled for the hypoxia tracer molecule iodoazomycin arabinoside ([123I]IAZA), to isotopes 131I (therapeutic) and 124I (PET imaging). Uncertainties introduced by the dissimilar isotope half-lives are discussed in detail. Radioisotope dosimetries for [123I]IAZA were obtained previously. These data are used here to calculate residence times for 131I and 124I and their uncertainties. We distinguish two cases when extrapolating to infinity: purely physical decay (case A) and physical decay plus biological washout (case B). Organ doses were calculated using the MIRD schema with the OLIDNA/EXM code. Significant increases in some organ doses (in mSv per injected activity) were found for 131I and 124I. The most affected organs were the intestinal walls, thyroid, and urinary bladder wall. Uncertainty remained similar to 123I for case A but considerably greater for case B, especially for long biological half-lives (GI tract). Normal tissue dosimetries for IAZA must be considered carefully when substituting isotope species. A long biological half-life can significantly increase dosimetric uncertainties. These findings are relevant when considering PET imaging studies with [124I]IAZA or therapeutic administration of [131I]IAZA.

Metabolism, Excretion, and Pharmacokinetics of Lorlatinib (PF-06463922) and Evaluation of the Impact of Radiolabel Position and Other Factors on Comparability of Data Across 2 ADME Studies.

While an initial clinical absorption, distribution, metabolism, and excretion (ADME) study (Study 1; N = 6) with 100 mg/100 µCi [14 C]lorlatinib, radiolabeled on the carbonyl carbon, confirmed that the primary metabolic pathways for lorlatinib are oxidation (N-demethylation, N-oxidation) and N-glucuronidation, it also revealed an unanticipated, intramolecular cleavage metabolic pathway of lorlatinib, yielding a major circulating benzoic acid metabolite (M8), and an unlabeled pyrido-pyrazole substructure. Concerns regarding the fate of unknown metabolites associated with this intramolecular cleavage pathway led to conduct of a second ADME study (Study 2; N = 6) of identical design but with the radiolabel positioned on the pyrazole ring. Results were similar with respect to the overall mass balance, lorlatinib plasma exposures, and metabolic profiles in excreta for the metabolites that retained the radiolabel in both studies. Differences were observed in plasma total radioactivity exposures (2-fold area under the plasma concentration-time curve from time 0 to infinity difference) and relative ratios of the percentage of dose recovered in urine vs feces (48% vs 41% in Study 1; 28% vs 64% in Study 2). In addition, an approximately 3-fold difference in the mean molar exposure ratio of M8 to lorlatinib was observed for values derived from metabolic profiling data relative to those derived from specific bioanalytical methods (0.5 vs 1.4 for Studies 1 and 2, respectively). These interstudy differences were attributed to a combination of factors, including alteration of radiolabel position, orthogonal analytical methodologies, and intersubject variability, and illustrate that results from clinical ADME studies are not unambiguous and should be interpreted within the context of the specific study design considerations.

Pivotal Considerations for Optimal Deployment of Healthy Volunteers in Oncology Drug Development.

Oncology drug development is among the most challenging of any therapeutic area, with first-in-human trials expected to deliver information on both safety and activity. Until recently, therapeutic approaches in oncology focused on cytotoxic chemotherapy agents, ruling out even the possibility of enrolling normal healthy volunteers (NHVs) in clinical trials due to safety considerations. The emergence of noncytotoxic modalities, including molecularly targeted agents with more favorable safety profiles, however, has led to increasing numbers of clinical pharmacology studies of these agents being conducted in NHVs. Beyond rapid enrollment and cost savings, there are other advantages of conducting specific types of studies in NHVs with the goal of more appropriate dosing decisions in certain subsets of the intended patient populations, allowing for enrollment of such patients in therapeutic trials from which they might otherwise have been excluded. Nevertheless, the decision must be carefully weighed against potential disadvantages, and although the considerations surrounding conduct of clinical trials using NHVs are generally well-defined in most other therapeutic areas, they are less well-defined in oncology.

Pharmacokinetics and Scintigraphic Imaging of the Hypoxia-Imaging Agent [123I]IAZA in Healthy Adults Following Exercise-Based Cardiac Stress †.

The objective of this work is to evaluate the potential effect of cardiac stress exercise on the accumulation of [123I]IAZA, a radiopharmaceutical used to image focal tissue hypoxia, in otherwise normal myocardium in healthy volunteers, and to determine the impact of exercise on [123I]IAZA pharmacokinetics. The underlying goal is to establish a rational basis and a baseline for studies of focal myocardial hypoxia in cardiac patients using [123I]IAZA. Three healthy male volunteers ran the 'Bruce' treadmill protocol, a clinically-accepted protocol designed to expose myocardial ischemia in patients. The 'Bruce' criterion heart rate is 85% of [220-age]. Approximately one minute before reaching this level, [123I]IAZA (5.0 mCi/0.85 mg) was administered as a slow (1-3 min) single intravenous (i.v.) injection via an indwelling venous catheter. The volunteer continued running for an additional 1 min before being transferred to a gamma camera. Serum samples were collected from the arm contralateral to the administration site at pre-determined intervals from 1 min to 45 h post injection and were analyzed by radio HPLC. Pharmacokinetic (PK) parameters were derived for [123I]IAZA and total radioactivity (total[123I]) using compartmental and noncompartmental analyses. Whole-body planar scintigraphic images were acquired from 0.75 to 24 h after dosing. PK data and scintigraphic images were compared to previously published [123I]IAZA data from healthy volunteers rest. Following exercise stress, both [123I]IAZA and total[123I] exhibited bi-exponential decline profiles, with rapid distribution phases [half-lives (t1/2α) of 1.2 and 1.4 min, respectively], followed by slower elimination phases [t1/2ß of 195 and 290 min, respectively]. Total body clearance (CLTB) and the steady state volume of distribution (Vss) were 0.647 L/kg and 185 mL/min, respectively, for [123I]IAZA and 0.785 L/kg and 135 mL/min, respectively, for total[123I]. The t1/2ß, CLTB and Vss values were comparable to those reported previously for rested volunteers. The t1/2α was approximately 4-fold shorter for [123I]IAZA and approximately 3-fold shorter for total[123I] under exercise relative to rested subjects. The heart region was visualized in early whole body scintigraphic images, but later images showed no accumulated radioactivity in this region, and no differences from images reported for rested volunteers were apparent. Minimal uptake of radiotracer in myocardium and skeletal muscle was consistent with uptake in non-stressed myocardium. Whole-body scintigrams for [123I]IAZA in exercise-stressed healthy volunteers were indistinguishable from images of non-exercised volunteers. There was no evidence of hypoxia-dependent binding in exercised but otherwise healthy myocardium, supporting the conclusion that exercise stress at Bruce protocol intensity does not induce measurable myocardial hypoxia. Effects of exercise on PK parameters were minimal; specifically, the t1/2α was shortened, reflecting increased cardiac output associated with exercise. It is concluded that because [123I]IAZA was not metabolically bound in exercise-stressed myocardium, a stress test will not create elevated myocardial background that would mask regions of myocardial perfusion deficiency. [123I]IAZA would therefore be suitable for the detection of viable, hypoxic myocardium in patients undergoing stress-test-based diagnosis.

Moderate Hepatic Impairment Does Not Affect Doravirine Pharmacokinetics.

Doravirine is a novel, potent, nonnucleoside reverse-transcriptase inhibitor currently in development for HIV-1 infection treatment. As a substrate for CYP3A-mediated metabolism, doravirine could potentially be affected by liver-function changes. As a portion of the HIV-1-infected population has varying degrees of liver impairment, we investigated the effect of moderate hepatic impairment on the pharmacokinetic profile and tolerability of single-dose doravirine 100 mg in otherwise healthy subjects. A total of 16 subjects aged 44-64 years took part in the open-label, single-dose trial: 8 with moderate hepatic impairment (Child-Pugh score, 7-9; 6 men, 2 women) and 8 healthy individuals (mean age and height matched with the impairment group; 6 men, 2 women). Subjects with hepatic impairment were required to have chronic, stable hepatic impairment with features of cirrhosis of any etiology. Blood sampling revealed that doravirine exposure was similar in both groups. The observed geometric least-squares mean ratio (90% confidence interval; moderately impaired/healthy subjects) was 0.99 (0.72-1.35) for AUC0-∞ , 0.93 (0.74-1.18) for AUC0-24 h , 0.90 (0.66-1.24) for Cmax , and 0.99 (0.74-1.33) for C24 h . Geometric mean apparent terminal t½ was ∼18 hours for both groups, whereas median Tmax was 2 hours (range, 1-6 hours) and 2.5 hours (range, 1-3 hours) for impaired and healthy individuals, respectively. In addition, doravirine was generally well tolerated. The results demonstrate that moderate hepatic impairment does not have a clinically meaningful effect on doravirine pharmacokinetics. Therefore, dose adjustment should not be necessary in patients with both HIV-1 and moderate hepatic impairment.

Coadministration of Rifampin Significantly Reduces Odanacatib Concentrations in Healthy Subjects.

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.

Absence of clinically relevant drug-drug interaction between odanacatib and digoxin after concomitant administration.

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.

Effects of Rifampin, a potent inducer of drug-metabolizing enzymes and an inhibitor of OATP1B1/3 transport, on the single dose pharmacokinetics of anacetrapib.

Anacetrapib is a novel cholesteryl ester transfer protein (CETP) inhibitor in development for treatment of dyslipidemia. This open-label, fixed-sequence, 3-period study was intended to evaluate the potential of anacetrapib to be a victim of OATP1B1/3 inhibition and strong CYP3A induction using acute and chronic dosing of rifampin, respectively, as a probe. In this study, 16 healthy subjects received 100 mg anacetrapib administered without rifampin (Day 1, Period 1), with single-dose (SD) 600 mg rifampin (Day 1, Period 2), and with multiple-dose (MD) 600 mg rifampin for 20 days (Day 14, Period 3). Log-transformed anacetrapib AUC0-∞ and Cmax were analyzed by a linear mixed effects model. The GMRs and 90% CIs for anacetrapib AUC0-∞ and Cmax were 1.25 (1.04, 1.51) and 1.43 (1.13, 1.82) for SD rifampin (Period 2/Period 1) and 0.35 (0.29, 0.42) and 0.26 (0.21, 0.32) for MD rifampin (Period 3/Period 1), respectively. Anacetrapib was generally well tolerated in both the absence/presence of SD and MD rifampin. In conclusion, treatment with SD rifampin, which inhibits the OATP1B1/3 transporter system, did not substantially influence the SD pharmacokinetics of anacetrapib, while chronic (20 days) administration of rifampin, which strongly induces CYP3A isozymes, reduced mean systemic exposure to SD anacetrapib by 65%.

Lack of a meaningful effect of anacetrapib on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: • Inhibition of cholesteryl ester transfer protein (CETP) is a potential new mechanism for the treatment of dyslipidaemia. Anacetrapib is a novel CETP inhibitor in development. Warfarin is a commonly prescribed anticoagulant that has a narrow therapeutic index. A drug interaction study for warfarin with a novel CETP inhibitor is expected to be helpful in defining dosing regimens. WHAT THIS STUDY: ADDS • This is the first study to show that there is no clinically meaningful pharmacokinetic interaction between anacetrapib and warfarin. The single dose pharmacokinetics and pharmacodynamics of orally administered warfarin were not meaningfully affected by multiple dose administration of anacetrapib, indicating that anacetrapib does not affect CYP 2C9 clinically. Thus, no dosage adjustment for warfarin is necessary when co-administered with anacetrapib. AIM: Anacetrapib is currently being developed for the treatment of dyslipidaemia. Since warfarin, an anticoagulant with a narrow therapeutic index, is expected to be commonly prescribed in this population, a drug interaction study was conducted. METHODS: In a randomized, open-label, two-period fixed-sequence design, 12 healthy male subjects received two different treatments (treatment A followed by treatment B). In treatment A, a single oral dose of 30 mg warfarin (3 × 10 mg Coumadin(TM) ) was administered on day 1. After a washout interval, subjects began treatment B, where they were given daily 100 mg doses of anacetrapib (1 × 100 mg) beginning on day -14 and continuing through day 7, with concomitant administration of 30 mg warfarin (3 × 10 mg) on day 1. All anacetrapib and warfarin doses were administered with a standard low fat breakfast. After warfarin concentrations and prothrombin time were measured, standard pharmacokinetic, pharmacodynamic and statistical (linear mixed effects model) analyses were applied. RESULTS: Anacetrapib was generally well tolerated when co-administered with warfarin in the healthy males in this study. The geometric mean ratios (GMRs) for warfarin + anacetrapib : warfarin alone and 90% confidence interval (CIs) for warfarin AUC((0-∞)) were 0.94 (0.90, 0.97) for the R(+) warfarin enantiomer and 0.93 (0.87, 0.98) for the S(-) warfarin enantiomer, both being contained in the interval (0.80, 1.25), supporting the primary hypothesis of the study. The GMRs warfarin + anacetrapib : warfarin alone and 90% CIs for the statistical comparison of warfarin C(max) were 1.01 (0.97, 1.05) for both the R(+) warfarin and the S(-) warfarin enantiomers, and were also contained in the interval (0.80, 1.25). The GMR (warfarin + anacetrapib : warfarin alone) and 90% CI for the statistical comparison of INR AUC((0-168 h)) was 0.93 (0.89, 0.96). CONCLUSION: The single dose pharmacokinetics and pharmacodynamics of orally administered warfarin were not meaningfully affected by multiple dose administration of anacetrapib, indicating that anacetrapib does not affect CYP 2C9 clinically. Thus, no dosage adjustment for warfarin is necessary when co-administered with anacetrapib.

Lack of an effect of anacetrapib on the pharmacokinetics of digoxin in healthy subjects.

Anacetrapib is currently being developed for the oral treatment of dyslipidemia. A clinical study was conducted in healthy subjects to assess the potential for an interaction with orally administered digoxin. Anacetrapib was generally well tolerated when co-administered with digoxin in the healthy subjects in this study. The geometric mean ratios (GMR) for (digoxin + anacetrapib/digoxin alone) and 90% confidence intervals (CIs) for digoxin AUC(0-last) and AUC(0-∞) were 1.05 (0.96, 1.15) and 1.07 (0.98, 1.17), respectively, both being contained in the accepted interval of bioequivalence (0.80, 1.25), the primary hypothesis of the study. The GMR (digoxin + anacetrapib /digoxin alone) and 90% CIs for digoxin C(max) were 1.23 (1.14, 1.32). Median T(max) and mean apparent terminal t(½) of digoxin were comparable between the two treatments. The single-dose pharmacokinetics of orally administered digoxin were not meaningfully affected by multiple-dose administration of anacetrapib, indicating that anacetrapib does not meaningfully inhibit P-glycoprotein. Thus, no dosage adjustment for digoxin is necessary when co-administered with anacetrapib.

Absence of food effect on the extent of alprazolam absorption from an orally disintegrating tablet.

STUDY OBJECTIVE: To evaluate the effect of a standardized meal on the bioavailability of alprazolam formulated as an immediate-release orally disintegrating tablet (ODT) in healthy volunteers. DESIGN: Single-dose, randomized, open-label, two-period crossover study. SETTING: Contract research organization clinic. SUBJECTS: Sixteen healthy volunteers (seven men, nine women), aged 20-50 years. Intervention. Subjects were administered a single dose of alprazolam ODT 1.0 mg during two treatment periods-under fasting conditions and after a standard high-fat breakfast-separated by a 7-day washout period, MEASUREMENTS AND MAIN RESULTS: Blood samples for determination of alprazolam pharmacokinetics were collected by venipuncture up to 72 hours after dosing. A validated liquid chromatography with tandem mass spectrometry detection method was used to quantify the alprazolam plasma concentration. The overall extent of alprazolam absorption from the ODT formulation, as measured by area under the concentration-time curve, was unaffected during fed conditions. However, the rate of alprazolam absorption was slower after administration during fed relative to fasted conditions. The mean maximum observed plasma concentration (Cmax) decreased approximately 25%, and time to Cmax (Tmax) was delayed approximately 1.5 hours when food was administered before dosing. CONCLUSION: Coadministration of food was shown to have no effect on extent of absorption of immediate-release alprazolam ODT 1.0 mg when compared with drug administration in the fasted condition; however, the rate of drug absorption was decreased. The clinical significance of the difference in rate of alprazolam absorption is unknown but thought to be minimal.

Safety, tolerability and pharmacokinetics of higher-dose mizoribine in healthy male volunteers.

AIMS: Mizoribine is an oral immunosuppressive agent approved in several countries for prevention of rejection in renal transplantation. Its therapeutic window is based on trough concentrations staying at > or =0.5 but <3 microg ml(-1). It has been postulated that as renal function returns to normal, higher doses may be needed to maintain efficacy than the current clinical dosage of 2-5 mg kg(-1) day(-1). The safety, tolerability and pharmacokinetics from two clinical trials of higher-dose mizoribine treatments in healthy male volunteers are presented. METHODS: Forty-eight healthy White male nonsmokers participated in two randomized, double-blind, placebo-controlled trials: 32 in a single-dose study (3, 6, 9 and 12 mg kg(-1)) and 16 in a multiple-dose study [6 mg kg(-1) day(-1) once daily for 5 days or twice daily (12 mg kg(-1) day(-1)) for 7 days]. Standard assessments of safety, tolerability and pharmacokinetics were performed. RESULTS: The safety profiles of both studies were generally unremarkable, except for elevated serum uric acid concentrations at the highest dose (12 mg kg(-1) day(-1)) in the multiple-dose study. Orally administered mizoribine reached peak concentrations within 2-3 h and was eliminated mostly via the kidney (65-100% of dose) with a 3-h half-life. Only the 12 mg kg(-1) day(-1) group achieved trough concentrations that were within the therapeutic window. Conclusions Based on the favourable safety profile and current pharmacokinetic information, a new starting dose in the 6-12 mg kg(-1) day(-1) range is recommended in the up to 3 months acute phase following transplantation, with dose reduction recommended only if the function of the transplanted kidney is impaired.

A single-dose, two-way crossover, bioequivalence study of dexmethylphenidate HCl with and without food in healthy subjects.

Attention deficit hyperactivity disorder (ADHD) in children is effectively treated by racemic oral methylphenidate (dl-MPH). The d-isomer (d-MPH) has been developed as an improved treatment for ADHD since only half the racemic dose is used. This study, performed in healthy subjects, assessed the effect of food on the pharmacokinetics of dexmethylphenidate hydrochloride (d-MPH HCl) in a single dose (2 x 10-mg tablets), two-way crossover with d-MPH administered to subjects in both a fasting state or after a high-fat breakfast. There were no serious or unexpected adverse events during the course of this study, with most events reported in comparable numbers of fed and fasted subjects. The bioequivalence of d-MPH was similar with or without food, with 90% confidence intervals of 88.2% to 104.6% and 105.9% to 118.2% for ln(C(max)) and ln[(AUC(0-infinity))], respectively. There was a marginal but statistically significant 1-hour increase in t(max) in the fed versus fasted state, reflecting an absorption delay. The rate of formation of the major metabolite, d-ritalinic acid (d-RA), was marginally decreased ( approximately 14%) after food. The extent of exposure to d-RA was similar (within 1.2%) between both treatments. There was a marginal but statistically significant difference in mean t(max) for d-RA between fed and fasted conditions, with peak concentration occurring 1.5 hours later after d-MPH administration with food. There was no measurable in vivo chiral inversion of d-MPH to l-MPH in plasma. In addition, the metabolism of d-MPH was stereospecific as d-MPH only produced d-RA. In summary, food had no substantial effect on the bioavailability of d-MPH, with an equivalent rate and extent of exposure obtained. Therefore, d-MPH can be administered without regard to food intake.

Lack of Interaction between Modified-Release Fluvastatin and Amlodipine in Healthy Subjects.

OBJECTIVE: To investigate the potential for a pharmacokinetic interaction between fluvastatin modified-release 80mg tablet (Lescol((R)) XL; fluvastatin XL) and amlodipine 5mg tablet (Norvasc((R))) following multiple once-a-day doses for 2 weeks. DESIGN: This was a single-centre, six-sequence, three-period, randomised, crossover design study. Fluvastatin XL 80mg tablet and amlodipine 5mg tablet were administered once a day for 2 weeks either alone or in combination. Fluvastatin and amlodipine serum concentration profiles were characterised on day 14 for each treatment. The pharmacokinetic interaction between the two drugs was evaluated based on the p-values and 90% confidence intervals (CIs) for log-transformed highest observed concentration (C(max)), area under the plasma concentration-time curve calculated by the linear trapezoidal method up to 24 hours (AUC(24)), and apparent oral clearance at steady state (CL/F), using a single entity as the reference treatment and the combination as the test treatment. Adverse events (AEs), safety laboratory tests and physical examinations were evaluated for safety. STUDY PARTICIPANTS: Twenty-four healthy subjects were enrolled and 19 completed the study. The safety analysis was based on data from all 24 subjects who received at least one dose of a treatment, while the pharmacokinetic analysis was based on data from the 19 subjects who completed all treatments. RESULTS: The coadministration of fluvastatin XL and amlodipine resulted in no significant changes in the steady-state AUC (469 vs 454 mug . h/L), C(max) (96 vs 89 mug/L), and CL/F (197 vs 232 L/h) of fluvastatin when compared with fluvastatin XL alone. The p-values for these comparisons were between 0.172 and 0.238, and the 90% CIs for the geometric means were within 78% and 139%. A similar comparison for amlodipine showed no significant difference in the steady-state AUC (132 vs 140 mug . h/L), C(max) (7.1 vs 7.5 mug/L) and CL/F (41 vs 40 L/h) of amlodipine. The p-values for these comparisons were between 0.309 and 0.353, and the 90% CIs for the geometric means were within 90% and 111%. The majority of the AEs were mild in severity. There were no clinically relevant changes in clinical laboratory results, physical examinations or vital sign parameters. CONCLUSION: There were no significant differences in the steady-state pharmacokinetics of fluvastatin or amlodipine when they were administered together and the small differences observed were not clinically relevant. Therefore, no dose adjustment of either drug is necessary when fluvastatin and amlodipine are coadministered.

Pharmacokinetics and electrocardiographic pharmacodynamics of artemether-lumefantrine (Riamet) with concomitant administration of ketoconazole in healthy subjects.

AIMS: To evaluate whether the potent CYP3A4 inhibitor ketoconazole has any influence on the pharmacokinetic and electrocardiographic parameters of the antimalarial co-artemether (artemether-lumefantrine) in healthy subjects. METHODS: Sixteen subjects were randomized in an open-label, two period crossover design study. Subjects received a single dose of co-artemether (day 1) either alone or in combination with multiple oral doses of ketoconazole (400 mg on day 1 followed by 200 mg o.d. for 4 additional days). Serial blood samples were taken and assayed for artemether and its main active metabolite dihydroartemisinin (DHA), and lumefantrine. RESULTS: The pharmacokinetics of artemether, its metabolite DHA, and lumefantrine were influenced by the presence of ketoconazole. AUC(0, infinity ) was increased from 320 to 740 ng ml-1 h (ratio 2.4, 90% CI 2.00, 2.86) for artemether, from 331 to 501 ng ml-1 h (ratio 1.7, 90% CI 1.40, 1.98) for DHA, and from 207 to 333 micro g ml-1 h (ratio 1.7, 90% CI 1.23, 2.21) for lumefantrine in the presence of ketoconazole. Cmax also increased in similar proportions for the three compounds (ratio 2.2 (90% CI 1.78, 2.83), 1.4 (90% CI 1.12, 1.74), and 1.3 (90% CI 0.96, 1.64), respectively). The terminal elimination half-life was increased for artemether (2.5 vs 1.9 h, 90% CI 1.12, 1.72) and DHA (3.1 vs 2.1 h, 90% CI 0.02, 3.36), but remained unchanged for lumefantrine (88 vs 95 h, 90% CI 0.81, 1.04). These increases in exposure to the antimalarial combination were much smaller than observed with food intake (up to 16 fold), and were not associated with increased side-effects or changes in electrocardiographic parameters. The study medications were well tolerated. CONCLUSIONS: The concurrent administration of ketoconazole with co-artemether led to modest increases in artemether, DHA, and lumefantrine exposure in healthy subjects. Dose adjustment of co-artemether is probably unnecessary in falciparum malaria patients when administered in association with ketoconazole or other potent CYP3A4 inhibitors.