Study design
Two phase 1, single-center (PPD Phase I Clinic, Austin, TX, USA), open-label, randomized, single-dose, 3-period crossover trials were conducted. In both studies, participants underwent screening evaluations to determine eligibility within 30 days of period 1 check-in. During the treatment period, participants were randomly assigned to 1 of 6 sequences of 3 treatments, each separated by a 6-day washout interval.
Each study received institutional review board approval (IntegReview Ethical Review Board, Austin, TX, USA) and was conducted in accordance with the Good Clinical Practice Guidelines of the International Conference on Harmonisation. All participants provided written informed consent. The two trials that were registered with ClinicalTrials.gov had the numbers: NCT02561650 and NCT02561741.
Study population
Inclusion criteria
Participants were men or nonpregnant, nonlactating women aged 18 to 55 years with health status considered by investigators as “healthy normal” at screening and check-in assessments. Participants had a body mass index 19 to 30 kg/m2 with a minimum weight of 110 lb (women) or 130 lb (men).
Exclusion criteria
Exclusion criteria included an acute illness within 14 days before period 1 check-in; electrocardiogram abnormalities; laboratory results falling outside of the upper or lower limits of normal; history of significant psychiatric illness requiring hospitalization, psychotherapy, and/or medication within the previous 3 years. Participants were also excluded if they had a history of any condition that might interfere with the absorption, distribution, metabolism, or excretion of the study drug.
Participants were excluded from the study if, during any study period, they experienced emesis any time after dosing at hour 0 through the 48-h postdose blood collection. This was to ensure that participants had adequate drug exposure to allow accurate assessment of pharmacokinetic parameters. Additional exclusion criteria included positive urine test results for drugs of abuse or alcohol; history of or treatment for substance abuse, narcotic addiction; use of nicotine-containing products within 6 months before period 1 check-in; and use of prescription drugs or nonprescription drugs, vitamins, minerals, or dietary/herbal supplements within 14 days before period 1 check-in and for the duration of the study. Finally, participants were excluded if they had undergone abdominal and/or pelvic surgery, including cholecystectomy, gastric bypass, or gastric band surgery, and cardiothoracic surgery.
Study treatments
IR/ER HB/APAP 7.5/325-mg tablets were given as a single 2-tablet dose (study 1) or a single 3-tablet dose (study 2) under fasted (reference) and fed (test) conditions. For their predose meals, participants received a US Food and Drug Administration–standardized high-fat meal with approximately 50 % of 1000 ± 100 cal coming from fat [treatment A], a low-fat meal with 25 to 30 % of 800 ± 80 cal coming from fat [treatment B] meal), or fasted (treatment C). To successfully complete the study, participants were required to complete all 3 periods (completers).
Assessments
Blood samples and pharmacokinetics
AUC from 0 h to time t (AUC0–t) and from time 0 extrapolated to infinity (AUC0–inf) and Cmax of hydrocodone and APAP were compared across the 3 treatments (high-fat meal, low-fat meal, and fasting). Time to Cmax (tmax), time to first measurable concentration (tlag), apparent first-order terminal elimination rate constant (Kel), and apparent plasma terminal elimination half-life (t1/2) were also assessed.
For determination of hydrocodone and APAP concentrations, whole blood samples (6 mL) were collected via venipuncture from each participant in prechilled lavender-top vacuum blood collection tubes containing K2EDTA anticoagulant. Blood was collected at predose (up to 60 min before dosing); after dosing at 15, 30, and 45 min: and at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 16, 18, 20, 24, 36, and 48 h. Blood samples were placed in an ice bath/cryoblock immediately after collection and centrifuged at approximately 4 °C. Within 1 h of collection, the plasma fraction was withdrawn by pipette, divided equally into 2 aliquots in labeled polypropylene screw-cap tubes, and frozen to ≤ −70 °C (study 1) or ≤ −20 °C (study 2). Samples were shipped from the PPD Phase I Clinic and remained frozen until received for assay at the PPD Bioanalytical Lab (Middleton, WI). A summary of the bioanalytical method is listed in an additional file (see Additional file 1). Hydrocodone and APAP concentrations were measured using a high-performance liquid chromatography/tandem mass spectrometry assay that was validated over a calibration range of 0.100 to 50.0 ng/mL for HC and a range of 100 to 50,000 ng/mL (study 1) or 15,000 ng/mL (study 2) for APAP. HC-d6 and APAP-d4 were used as the internal standards. Study data were collected using the Analyst Version 1.4.2 (Applied Biosystems, Carlsbad, CA) and PPD Assist LIMS Version 5 (PPD, Richmond, VA). The assay method was validated for linearity, precision, accuracy, ruggedness, recovery, and specificity. Studies to confirm both short-term stability and long-term storage stability were performed. Analyses of samples were performed following the principles of Good Laboratory Practice and PPD’s standard operating procedures.
Safety and tolerability
Treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), vital signs, and pulse oximetry were assessed at baseline and throughout the 48 h after dosing. TEAEs, treatment-related TEAEs, severity of TEAEs, and TEAEs leading to early discontinuation were summarized by system organ class and were coded using the Medical Dictionary for Regulatory Activities, version 14.0. Physical examinations were performed at screening, check-in to each study period, and at study exit or early termination. A 12-lead electrocardiogram and laboratory tests (chemistry, hematology, and urinalysis) were performed at screening and final visit or early termination.
Statistical methods
Blood samples and pharmacokinetics
Individual plasma concentration versus time data were used to estimate the pharmacokinetic parameters of hydrocodone and APAP by standard noncompartmental methods. Pharmacokinetic parameters were summarized by treatment using descriptive conditions. Geometric means were included for AUC0–t, AUC0–inf, and Cmax.
To analyze the effect of food, an analysis of variance using the SAS/STAT® version 9.1.3 (SAS Institute, Cary, NC) general linear mixed model procedure was conducted with the natural log-transformed pharmacokinetic parameters (AUC0–t, AUC0–inf, and Cmax) as the dependent variables, with sequence, treatment, and period as fixed effects and participants nested within sequence as a random effect. Treatment A (fed condition, high-fat meal) was compared to Treatment C (fasted condition), Treatment B (test: fed condition, low-fat meal) was compared to Treatment C (reference: fasted condition), and Treatment A (test: fed condition, high-fat meal) was compared to Treatment B (reference: fed condition, low-fat meal). A 90 % confidence interval (CI) of the geometric least squares mean (LS mean) ratio fully contained within 80.00 to 125.00 % for AUC0–t, AUC0–inf, and Cmax indicated no difference between each treatment.
The Wilcoxon signed-rank test was performed to evaluate differences in tmax and tlag, with a P value ≤0.05 indicating a significant difference between treatments.
Safety and tolerability
Safety was assessed in all participants who received ≥1 dose of study drug (all dosed participants). All TEAEs were summarized using descriptive statistics.