Bioavailability of oxycodone after administration of a new prolonged-release once-daily tablet formulation in healthy subjects, in comparison to an established twice-daily tablet (2024)

Study design and formulations

Three studies were conducted as single-center, open-label, randomized, balanced, two-treatment, two-period, two-sequence crossover studies. Washout periods of at least 7 days separated the two treatment periods in each study. The first study considered a once-daily administration of OOD and a twice-daily administration of OTD under fasting conditions (study 1, EudraCT-No.: 2008-008216-19) and the second study considered these under fed conditions (study 2, EudraCT-No.: 2009-012646-24). The third study included multiple-dose administration of OOD and OTD (study 3, EudraCT-No.: 2009-012648-17).

Products under investigation in all three studies were the 10-mg strength of a new OOD tablet formulation as test product (named Oxycodone HCl 10-mg PR tablets XL (Develco Pharma Schweiz AG)) and the 5-mg strength of an established OTD tablet formulation as reference product (traded Oxygesic 5-mg Retardtabletten, Mundipharma GmbH, Limburg an der Lahn, Germany).

The test product is a prolonged-release multiple-unit pellet formulation intended for administration every 24 hours. Available tablet strengths of 10 mg, 20 mg, 40mg, and 80 mg showed dose proportionality [11]. The new formulation is designed to also have abuse-deterrent properties regarding expected methods of abuse (crushing, heating, snorting and intravenous application) and to also have alcohol-resistant properties regarding misuse by concomitant alcohol consumption [12].

The reference product is a matrix formulation where the release of oxycodone is biphasic with an initial relatively fast release followed by a more controlled release [7, 8, 13].

The reference product is approved for administration every 12 hours and is labelled as a prolonged-release tablet, but is also referred to as controlled release [13, 14, 15].

Subjects

In each of the three studies, 36 healthy male and female Caucasian subjects between 18 and 55 years of age with a BMI of 19–28kg/m² were enrolled. Female subjects had to use contraception and undergo pregnancy tests before and during the study. Assessment of subjects’ health was based on medical and medication history, physical examinations, 12-lead electrocardiogram, and clinical laboratory testing. Main exclusion criteria were smoking (> 10 cigarettes per day), intake of any medication (prescribed or over-the-counter, including herbal remedies) up to 2weeks before first study medication administration, history of compulsive alcohol (≥10drinks weekly) and/or regular drug abuse, and any health conditions where opioids are contraindicated. Written informed consent was obtained from all subjects prior to inclusion. The studies were approved by the Hungarian Medical Research Council Ethics Committee for Clinical Pharmacology and were performed in accordance with regulatory and legal requirements, Good Clinical Practice guidelines [16], and the Declaration of Helsinki [17].

Study procedures

In each treatment period of study 1 and study 2, subjects were required to stay at the clinical unit for at least 12 hours before the morning administration and were discharged 24 hours thereafter. Subjects returned to the clinical unit for blood sampling 30, 36, and 48 hours after the morning administration. In each treatment period of study 3, subjects were required to begin their stay at the clinical unit at least 12 hours before first administration, ending their stay in the morning of day 5 (i.e., 12 hours after last administration). On blood sampling days, the subjects swallowed the medication in a seated position and then stayed in a semireclined position until 3hours post-dose.

Study 1 (fasting conditions): At 07:00 AM, after at least a 10-hour overnight fast, the subjects received either 1 tablet of OOD 10mg or the first tablet of OTD 5mg. Twelve hours after the first dose, the second tablet of OTD 5 mg was administered. A standardized light breakfast and a cooked lunch were served 3 hours and 6 hours after morning dose, respectively. Dinner was served 15 hours after morning dose.

Study 2 (fed conditions): Between 06:30 and 06:50 AM, after an overnight fast of at least 10 hours, the subjects consumed a standard high-fat, high-calorie breakfast as recommended by the US Food and Drug Administration [18]. Afterwards, either OOD 10 mg or the first tablet of OTD 5 mg was administered. Twelve hours after the first dose, the second tablet of OTD 5 mg was administered. A cooked lunch was served 6 hours and a dinner 15 hours after morning dose.

Study 3 (multiple-dose administration): On 4 consecutive days at 07:00 AM and after at least a 10-hour overnight fast subjects received either OOD 10 mg or the first tablet of OTD 5 mg. Twelve hours after the first dose, the second tablet of OTD 5 mg was administered. Standard meals were consumed 3, 6, and 15 hours after morning dose.

Blood sampling

To determine blood plasma concentrations of oxycodone in study 1 and study 2, blood samples were collected at 0 (pre-dose), 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 6.0, 7.0, 8.0, 10.0, 12.0, 14.0, 16.0, 20.0, 24.0, 30.0, 36.0, and 48.0hours post OOD administration and at 0 (pre-dose), 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 6.0, 7.0, 8.0, 10.0, 12.0, 12.5, 13.0, 13.5, 14.0, 14.5, 15.0, 15.5, 16.0, 16.5, 17.0, 18.0, 19.0, 20.0, 22.0, 24.0, 30.0, 36.0, and 48.0 hours post OTD administration. More frequent samples were collected between 12 and 24 hours after the morning OTD dose to describe the profile for the evening OTD dose.

In the multiple-dose study, study 3, pre-dose blood samples were collected on days 1–4, and postdose blood samples were collected on day 4 at the same time point as in studies 1 and 2, until 24 hours postdose.

Blood samples were collected into vacutainers, immediately cooled in an ice bath, and centrifuged within 30 minutes. Plasma was transferred and stored at –20 °C until analysis.

Bioanalysis

Oxycodone plasma concentrations were quantified using a validated method [19] that used a liquid-liquid extraction for sample preparation and liquid chromatography with tandem mass spectrometry detection (LC-MS/MS API 2000, PE Biosystems, Foster City, CA, USA) for sample measurement. Oxycodone was selectively quantified by using multiple-reaction monitoring as detection mode, hydromorphone was used as internal standard. The calibration curve of oxycodone ranged from 0.5 to 100.0 ng/mL. The lower limit of quantitation (LLOQ) was 0.5 ng/mL. Range of intraday precision was determined as 2.6–5.6% for 80.0 ng/mL, as 2.0–8.3% for 10.0 ng/mL, as 3.4–4.4% for 1.0 ng/mL, and as 3.6–6.9% for 0.5 ng/mL. Interday precision was 5.6% for 80.0 ng/mL, 6.5% for 10.0 ng/mL, 3.6% for 1.0 ng/mL, and 6.5% for 0.5 ng/mL. Range of intraday accuracy was determined as –0.1to9.4% for 80.0 ng/mL, as –6.0to3.0% for 10.0 ng/mL, as –2.0to0.0% for 1.0 ng/mL, and as 0.8to11.8% for 0.5 ng/mL. Interday accuracy was 5.6% for 80.0 ng/mL, –2.0% for 10.0 ng/mL, –1.0% for 1.0 ng/mL, and 6.2% for 0.5 ng/mL.

Stability was investigated and documented for storage of stock solution (up to 11 weeks at 2–8 °C), for three thaw/freeze cycles, for plasma sample processing (up to 6 hours at room temperature), for autosampler waiting time (up to 24 hours at 2–8 °C), and for long-term storage (up to 9 months at –20°C).

Pharmaco*kinetic data evaluation

Pharmaco*kinetic parameters for oxycodone were calculated by standard noncompartmental methods (WinNonlin Version 5.2.1, Pharsight Corporation, Mountain View, CA, USA).

Pharmaco*kinetic parameters were chosen in order to describe and compare the bioavailability of OOD and OTD as well as to investigate the influence of food on the bioavailability of each formulation.

As primary parameter for describing the extent of bioavailability, the area under the plasma concentration time curve (AUC) was calculated in study 1 and study 2 for OOD and OTD as AUC_(0–t) (from time 0 to last measured concentration (t)) and as AUC_(0–∞) (from time 0 to infinity), whereby for OTD the AUC considered the sum of the administrations in the morning and in the evening. Residual area (%) was calculated using the formula (AUC_(0–∞)–AUC_(0–t)) × 100/AUC_(0–∞). Additionally, for OTD, AUC_(0–12h) was calculated for assessment of influence of food. In study 3, AUC was evaluated for OOD and OTD as AUC_ss(0–24h) (from time 0 to 24 hours) considering for OTD the sum of the two 12-hour dosing intervals.

As secondary parameters, the maximum plasma concentration (C_max), the corresponding time to reach maximum plasma concentration (t_max), and the elimination half-life (T_1/2) were evaluated in study 1 and study 2, in addition, the concentration at the end of the dosing interval (C_τ,ss,24h), the half value duration (HVD), and the peak-trough fluctuation (PTF) were evaluated in study 3.

C_max and t_max were evaluated in study 1 and study 2 for OOD and OTD as C_max(0–t) and as t_max(0–t). Additionally, C_max(0–12h) and t_max(0–12h) were evaluated for assessment of food effect of OTD. In study 3, C_max was evaluated for OOD and OTD as C_{max,ss(0–24h)}.

T_1/2 was calculated within study 1 and study 2 by using the formula ln(2)/λ_z whereby the terminal rate constant λ_z was obtained by linear regression using log-transformed plasma concentrations of the terminal elimination phase.

After multiple-dose administration (study 3) the concentrations at the end of the dosing intervals were evaluated for OOD and OTD as C_τ,ss,24h.

The half-value duration reflects the duration in which the plasma concentration is at or above 50% of maximum plasma concentration (also referred to as T50% C_max) [20] and was calculated in study 3 for OOD and OTD as HVD_ss(0–24h).

The peak-trough fluctuation was calculated by using the formula (C_{max,ss(0–24h)}–C_{min,ss(0–24h)})/C_{av,ss(0–24h)} whereby C_{av,ss(0–24h)} was obtained by the formula AUC_ss(0–24h)/24h.

Statistical analysis

Statistical analyses were performed using SAS 9.1.3 (SAS Institute Inc., Cary, NC, USA).

To compare bioavailability of OOD and OTD, 90% confidence intervals (CIs) were calculated for AUC_(0–t) and C_max(0–t) (study 1 and study 2) and for AUC_ss(0–24h), C_{max,ss(0–24h)}, and C_τ,ss,24h (study 3). Logarithmic transformations were applied for analysis of variance (ANOVA). 90% CIs for the difference between drug formulation least-squares means (LSM) were calculated. Comparability between OOD and OTD was assumed if the retransformed CIs of the different parameters were within the acceptance range of 80.00–125.00%.

To assess the influence of food on bioavailability of OOD or OTD, results of study 1 (fasting conditions) and study 2 (fed conditions) were compared and statistically handled as interstudy comparison by using a parallel-group design. This procedure was justified because the population of subjects, blood sampling points, study procedures, clinical unit, and bioanalytical method were the same for both studies. AUC_(0–t) and C_max(0–t) of OOD and AUC_(0–12h) and C_max(0–12h) of OTD were chosen to compare the results obtained under fasting or fed conditions for the respective formulation. Non-zero log-transformed data were used for ANOVA. Data were subjected to a one-way ANOVA using the SAS GLM procedure for the estimation of the LSM of the factor “condition”. 90% CIs for the difference between drug formulation geometric least-squares means (LSMEANS) were calculated for the log-transformed parameters.

Safety assessment

Study subjects were monitored for changes in health status and clinical parameters. Physical examination including vital signs, 12-lead electrocardiogram, and routine clinical laboratory test (i.e., hematology, clinical chemistry, serology, urinalysis) were performed at screening and at follow-up. Prior to each treatment period, tests for pregnancy, vital signs, and electrocardiogram were performed. Prior to each blood sampling (including screening and follow-up), subjects were questioned about adverse events (AEs).

Demographic data of subjects

Demographic data of the subjects of the studies are summarized in Table 1. In each study, 36 subjects were enrolled and completed the study. There were no withdrawals or drop outs. In terms of age, body mass index, weight, and height there were no obvious differences between the collectives of the three studies.

Comparison of bioavailability

Mean plasma concentration-time curves of oxycodone after administration of OOD and OTD are presented in Figure 1 (study 1: fasting conditions), ​conditions),22 (study 2: fed conditions), and Figure 3 (study 3: multiple-dose administration).

For both OOD and OTD, similar shapes of curves could be observed under fasting and fed conditions (Figures 1, ​,2).2). During the absorption phase, increase of concentrations are slower for OOD than for OTD, which is characterized by a rapid absorption. Shape of curves of OOD reveal a continuous increase, and maximum plasma concentrations are reached between 8 and 12 hours after administration. Maximum plasma concentrations of OTD are reached after the morning dose as well as after the evening dose between 2 and 4 hours after administration. Within the elimination phase, the plasma profiles between OOD and OTD are similar.

After multiple-dose administration of OOD and OTD, plasma concentrations of oxycodone are comparable between both formulations before administration on day 4 (Figure 3). The shapes of the plasma profiles confirmed the observations from study 1 and study 2.

Pharmaco*kinetic parameters of oxycodone following administration of OOD and OTD under fasting and fed conditions are given in Table 2 and, after multiple dose administration, in Table 3. Within the single-dose studies (study 1 and study 2), blood sampling over the time period of 48 hours was sufficient, and LLOQ was low enough so that residual area was lower than 20%. Furthermore, AUC_(0–t) covered more than 80% of AUC_(0–∞) in 140 of 144 individual plasma concentration-time curves. The wash-out phase of 7 days covers more than 14 elimination half-lives and was therefore long enough to avoid predose concentrations in the second study period.

The geometric mean ratios and 90% CIs of AUC, C_max, and C_τ,ss,24h are provided in Table 4 for comparison of the bioavailability of OOD and OTD. The results demonstrate that all calculated CIs are within the acceptance range of 80.00–125.00%.

Influence of food on bioavailability

The pharmaco*kinetic parameters for the investigation of the influence of food on bioavailability of OOD (AUC_(0–t) and C_max(0–t)) and OTD (AUC_(0–12h) and C_max(0–12h)) are listed in Table 2. The corresponding geometric mean values and 90% CIs are summarized in Table 5. The results show that for OOD the geometric mean ratio does not differ for the extent of bioavailability (AUC_(0–t)) and is ~13% higher for C_max(0–t) under fed conditions in comparison to fasting conditions. The geometric mean ratios for OTD are ~ 29% and 34% higher for AUC_(0–12h) and C_max(0–12h) under fed conditions in comparison to fasting conditions, respectively.

Safety

In all three studies, no serious or otherwise significant AEs or fatalities were reported, and no volunteers discontinued due to an AE. From the total 108 exposed subjects, 8subjects experienced 9 AEs while on OOD, and 13 subjects experienced 13 AEs while on OTD.

Study 1 (fasting conditions): With 4 observed AEs related to treatment in 3 subjects (1 case each of nausea, headache, vomiting, and itching; all classified as mild or moderate), both treatments were well tolerated when applied in fasted state.

Study 2 (fed conditions): Minor safety issues with 11 treatment-related AEs in 11 subjects were observed. Those included headache (n = 7), itching (n = 3), and nausea (n = 1). One was considered moderate, the others as mild.

Study 3 (multiple-dose administration): 7 AEs in 7 subjects were reported as treatment-related including headache (n = 5) and itching (n = 2). All were of mild intensity.

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