Pharmacokinetics and Bioavailability of a Fixed-Dose Combination of Ibuprofen and Paracetamol after Intravenous and Oral Administration

This study was a phase I, single-centre, single-dose, open-label, randomized, five-way cross-over trial in 30 healthy adult participants. After an initial screening period of up to 28 days, there were five study periods, separated by washout periods of at least 48 h, and a subsequent final follow-up period of up to 7 days. The research was conducted in accordance with Good Clinical Practice (GCP), including the Declaration of Helsinki and all applicable regulatory requirements. The study protocol received approval by the Health and Disability Ethics Committee, Ministry of Health, New Zealand, and the trial was registered with the Australian New Zealand Clinical Trial Registry (trial ID: ACTRN12614000809639).

Healthy volunteers of both genders, 18–50 years of age with a body mass index (BMI) of 18.0–32.0 kg/m², were recruited from the Christchurch Clinical Studies Trust databases. Informed consent was obtained by the principal investigator from all individual participants included in the study prior to the screening visit. Screening involved a physical examination and recording of demographic data, vital signs, the medical history and concomitant medications. A blood sample was taken for haematology, biochemistry and serology screening, and a urine sample was collected for urinalysis, and illicit-drug and alcohol breath screening tests were performed. Suitable participants had to comply with all study inclusion and exclusion criteria (presented in Table 1).

Participants were randomized in a cross-over fashion to a study sequence of four IV doses and one oral dose, using a computer-generated list prior to commencement. For all doses, participants were confined to the study centre from the previous evening to approximately 12 h after study drug administration. The study drug was administered in the morning, following a 10-h fast, and a standard lunch and snacks were provided at 4 and 8 h after study drug administration, respectively.

Patients received each of the following five treatments in a randomized order:

Treatments A, B, C and D were manufactured by SM Farmaceutici SRL, Italy, and administered as a slow IV infusion over 15 min into an indwelling cannula. Treatment E was manufactured by Sigma Laboratories, India, and administered orally with 240 mL of water.

Blood samples (approximately 5 mL) for pharmacokinetic analysis were collected into lithium–heparin tubes. The blood sampling schedules were different for the IV and tablet formulations, as outlined below:

All haematology, biochemistry and urinary analyses were conducted using standard methodologies within a single laboratory. Plasma concentrations of paracetamol and ibuprofen in human plasma (lithium–heparin) were determined using validated liquid chromatography–tandem mass spectrometry (LC–MS/MS) procedures.

Paracetamol plasma concentrations were analysed using API 3000 and Quattro premier mass spectrometry in multiple reaction monitoring (MRM) mode, using a turbo ion spray with positive ionization. The chromatographic separation of paracetamol employed a C₁₈ column, using a mobile phase consisting of de-ionized water, formic acid and acetonitrile. The calibration curves were linear over the working range of 50–20,000 ng/mL, with a regression coefficient (R ²) of ≥0.99937. The lower limit of quantification (LLOQ) was 50 ng/mL (precision 3.44 %, accuracy 93.69 %).

Ibuprofen plasma concentrations were analysed using a Sciex API 3000 and API 4000 triple quadrupole mass spectrometer in MRM mode, using a turbo ion spray with negative ionization. Selective analysis of ibuprofen was achieved on a Symmetry C₁₈ column by using a mobile phase consisting of ammonium formate, methanol and acetonitrile. The calibration curves were linear over the concentration range of 50–35,000 ng/mL, with an R ² of ≥0.9975. The LLOQ was 50 ng/mL (precision 8.85 %, accuracy 104.25 %). These methods have also been described elsewhere [10].

The pharmacokinetic parameters of paracetamol and ibuprofen were calculated using Excel 2013. C _max and the time to reach C _max (T _max) were determined directly from the raw data. The elimination rate constant (k _e) was calculated from the slope of the linear relationship between the log_e concentration and the time during the terminal elimination phase. AUC from time zero to the time of the last measurable plasma concentration (AUC _t ) was calculated by the linear trapezoidal rule, and AUC from time zero to infinity (AUC_∞) was calculated after extrapolation from time t to infinity as the ratio of the last measurable plasma concentration (C _last) to k _e. The elimination half-life (t _½) was estimated from the elimination rate constant as ln(2)/k _e.

Statistical analysis was performed using the validated program SPSS v22.0. The ratios used to test bioequivalence were calculated from log_e-transformed data for C _max, AUC _t and AUC_∞. The differences between the log_e means and the 90 % confidence intervals (CIs) of the differences, derived from the residual variance from the analysis of variance (ANOVA) model, were back-transformed to estimate the ratios of the two formulations and the 90 % CIs of these ratios.

Safety was assessed in terms of the overall proportion of subjects with adverse events (AEs) and by haematological and biochemical assessment of blood samples. AEs were evaluated for their severity (mild, moderate or severe) according to the subjective impact they had on the performance of daily activities and their likely relationship to the medication (not related, unlikely, possibly, probably or definitely related) according to the likelihood of a temporal association between the onset of the event and the administration of the medicinal product.

Thirty subjects were enrolled in this study; 23 (77 %) were male, and all were Caucasian. The mean (± standard deviation) age and BMI were 29.9 (±19.4) years and 24.5 (±2.9) kg/m², respectively. Twenty-nine participants completed the study, each of whom received all five treatments and was included in the pharmacokinetic analysis.

The mean paracetamol plasma concentration–time curves for ibuprofen and paracetamol are presented in Figs. 1 and 2, respectively. A tabulated summary of the pharmacokinetic data for both compounds is also presented in Table 2.

Intravenous infusions resulted in mean C _max values of 26,709.6 ng/mL (FDC-IV) and 26,236 ng/mL (paracetamol IV) immediately after the 15-min infusion. A half dose of FDC-IV provided a mean C _max of 12,880 ng/mL. The concentration of paracetamol from the FDC-oral tablets peaked at 0.73 h, with a mean C _max of 14,907 ng/mL. The oral route provided paracetamol C _max values 44 % lower than those observed after administration of FDC-IV or paracetamol IV.

Similarly, IV infusions resulted in C _max values of 39,506.7 ng/mL (FDC-IV) and 40,292.97 ng/mL (ibuprofen IV) immediately after the 15-min infusion. A half dose of FDC-IV provided a mean C _max of 20,352 ng/mL. The concentration of ibuprofen from the FDC-oral tablets peaked at 1.49 h, with a mean C _max of 19,637 ng/mL. The oral route provided ibuprofen C _max values 50 % lower than those observed after administration of FDC-IV or ibuprofen IV.

The corresponding AUC _t and AUC_∞ values were very similar across both the full-dose IV formulation and the FDC-oral tablets. The back-transformed 90 % CIs for FDC-IV in comparison with paracetamol IV and ibuprofen IV all fell within the 80–125 % acceptable bioequivalence range, thus confirming the lack of any pharmacokinetic interaction when both paracetamol and ibuprofen are given in combination as a parenteral preparation (Table 3).

Comparisons of the C _max, AUC _t and AUC_∞ values for FDC-IV and a half dose of FDC-IV demonstrated consistent dose proportionality for both paracetamol and ibuprofen (Table 4). The t _½ values for paracetamol and ibuprofen were found to be comparable between all treatment groups (Table 2).

The relative bioavailability of paracetamol and ibuprofen from the FDC-oral tablets was calculated from the back-transformed ratios of the log_e means of the AUC_∞ values for the oral and IV formulations (AUC_FDC-oral/AUC_FDC-IV). For FDC-oral, the relative bioavailability of paracetamol was 93.78 % (90 % CI 90.98–96.67 %) and the absolute bioavailability of ibuprofen was 96.45 % (90 % CI 93.13–99.89 %), suggesting nearly complete absorption of both compounds from the gastrointestinal mucosa. These results are summarized in Table 5.

Twenty-five non-serious AEs were reported by 15 subjects (50 %). The majority of AEs were mild (80 %), and all other AEs were moderate (20 %). There were no severe AEs. Seventy-six percent of AEs were not related to the study medication in that a temporal association between the onsets of the events relative to the administration of the product was not reasonable. Twenty-four percent of AEs had a reasonable temporal relationship between their onset and administration of the study medication, and were deemed either ‘unlikely related’ or ‘possibly related’ on the basis of the subjective likelihood of the association. These data, and the distribution of AEs across the study periods (study drug or washout), are presented in Table 6. One subject did suffer a serious AE: bilateral ankle fractures due to a fall.

The results of this study demonstrate that concurrent administration of ibuprofen and paracetamol in a novel IV fixed-dose combination did not significantly alter the extent of absorption of ibuprofen or paracetamol, in comparison with either agent alone. A lack of a pharmacokinetic interaction between ibuprofen and paracetamol has been documented for the following oral formulation, fixed-dose combinations: ibuprofen 300 mg + paracetamol 1000 mg [10], ibuprofen 400 mg + paracetamol 1000 mg [11] and ibuprofen 400 mg + paracetamol 650 mg [12]. In these products, after oral administration, the values of the pharmacokinetic parameters C _max, AUC _t and AUC_∞ for both ibuprofen and paracetamol were similar with the fixed-dose combinations and monotherapies, and the back-transformed 90 % CI for each parameter fell within the acceptable bioequivalence range (80–125 %) [10, 11]. Similar results were obtained from comparison of pharmacokinetic parameters by ANOVA for the third fixed-dose combination [12]. Consequently, the results from the present study confirm and extend such results for an IV formulation.

The dose proportionality of the FDC-IV formulation provided here is consistent with that reported for IV ibuprofen; a twofold lesser dose results in decreases of 44–51 % in C _max, AUC _t and AUC_∞ [6, 14]. Absorption of paracetamol from a half dose of FDC-IV appeared to be slightly delayed; however, the longer mean T _max in this group was due to a single patient whose paracetamol C _max occurred 20 min after the start of the 15-min infusion (5 min after the end of the infusion). The clearance of both compounds remained constant (2.4 h for paracetamol and 1.8 h for ibuprofen), which is consistent with previous findings for ibuprofen [6]. The clear dose proportionality of absorption of both active ingredients in FDC-IV could provide practitioners with the ability to easily titrate analgesia according to their patient’s pain.

This study determined that both active ingredients in the FDC-oral formulation have very high bioavailability. In comparison with FDC-IV, the relative bioavailability values for ibuprofen and paracetamol in the FDC-oral tablets are 93.59 and 96.34 % respectively, confirming the assertion that both compounds are not subject to significant pre-systemic metabolism. These results are congruent with previously published data [5‐9].

Absorption via the gastrointestinal mucosa results in delayed absorption and decreased C _max values. In comparison with FDC-IV, the C _max values for ibuprofen and paracetamol were reduced by 50 and 44 %, respectively, after administration of FDC-oral. For ibuprofen, the results of this study are in line with other published data; an equivalent oral dose of ibuprofen results in a C _max value that is 50 % of the value observed after an IV dose (63 versus 120 µg/mL) [5]. For paracetamol, oral dosing has been shown to reduce C _max of paracetamol 1000 mg by 41–43 % in healthy volunteers [9, 13].