Leonor Laredo-Velasco

Background: Drug combinations with complementary mechanisms of action are able to achieve effective analgesia at lower doses, thereby reducing the risk of adverse effects (AEs). This study evaluated the analgesic efficacy and tolerability of two fixed-dose combinations (FDCs) of ibuprofen/tramadol (IBU/TRA) compared with tramadol and a placebo. Methods: This multicenter, randomized, double-blind, dose-finding, pilot clinical trial compared IBU/TRA (400/37.5 mg and 400/75 mg) with 100 mg of tramadol and a placebo in patients with moderate-to-severe pain following dental surgery. The primary endpoints were pain intensity at 6 h (PI_6h) and the pain intensity difference from baseline to 6 h (PID_6h). PID_7h, the sum of pain intensity differences from baseline to 7 h (SPID_0–7h), pain relief (PAR_7h), total pain relief (TOTPAR_7h), the use of rescue medication and AEs were also assessed. Results: Seventy-two patients were randomized and evaluated. Both FDCs showed superiority over the placebo for PI_6h and PID_6h (p < 0.05) but were not significantly different from 100 mg of tramadol. The statistical superiority of FDCs over the placebo was observed for PID_7h, SPID_0–7h, PAR_7h and TOTPAR_7h. The percentage of patients receiving rescue medication was higher in the placebo (94.1%) and tramadol (52.6%) groups than the FDC groups (35.3% and 36.8% for 400/37.5 mg and 400/75 mg, respectively). A post hoc analysis showed that the FDCs had a superior analgesic efficacy to 100 mg of tramadol in the SPID_0–4h (p < 0.005). The incidence of AEs was comparable between treatment groups. Conclusions: Both FDCs of IBU/TRA provided superior analgesic efficacy compared to the placebo. We propose using SPID_0–4h as the preferred variable for evaluating the efficacy of this type of drug combination.

Objective: This study aimed to assess the bioequivalence of two oral methocarbamol formulations, as follows: the test (T) methocarbamol 1500 mg tablets and the reference (R) Robaxin® 500 mg tablets (3 tablets, total dose: 1500 mg) under fasting conditions, and compare their pharmacokinetic performance. Methods: This was a single-center, phase I, randomized, open-label (blinded for analytical determination), two-sequence, two-period, crossover, bioequivalence study. A total of 32 healthy volunteers were randomly assigned to receive the T-R or R-T administration sequence. Each volunteer received a single dose of each methocarbamol formulation (T or R) separated by a washout period of 7 days. To evaluate the pharmacokinetic profile, blood samples were collected at nineteen time points after dosing. Results: The arithmetic mean Cmax was 31.72 µg/mL for R and 32.39 µg/mL for T, and the arithmetic mean AUC0−t was 90.25 h × µg/mL and 89.72 h × µg/mL, respectively. All adverse events reported were mild for both formulations. The 90% confidence intervals for the corresponding logarithmically transformed geometric mean ratios of Cmax and AUC0−t fell within the acceptance interval of 80.00–125.00%, as their values were 91.67–112.47% for ln(Cmax) and 92.34–103.47% for ln(AUC0−t). Conclusion: Therefore, one tablet of methocarbamol 1500 mg was found to be bioequivalent to the Robaxin® 500 mg tablets (3 tablets), with comparable tolerability and safety profiles.

Background/Objectives: Using a combination of analgesics allows for the use of lower doses of each, therefore, lowering risk of side effects. The study aims to estimate the bioavailability (pharmacokinetics of enantiomers and metabolites, as well as linearity and sex-related effects) of fixed doses combinations of Ibuprofen/Tramadol via an intravenous (IV) vs. oral route, and it is interesting to bridge the gap of equipotent doses by different routes. Methods: This was a randomized, open-label, crossover, five-period pharmacokinetics clinical trial, in which a single dose of each formulation [four different strengths of Ibuprofen 400 mg/Tramadol HCl (30, 31.5, 33, 37.5 mg), intravenous; Ibuprofen/Tramadol HCl 400 mg/37.5 mg, granules for oral solution], were administered to healthy volunteers. Enantiomers of Ibuprofen, of Tramadol, and of its main active metabolite O-desmethyl-Tramadol (M1) were measured, and pharmacokinetic parameters (maximal concentration (Cmax) and area under the concentration curve (AUC)) were estimated. Given the exploratory nature of the study, the sample size was small to provide sufficient power for comparisons of differences across all subgroups. The study was registered at Spanish register of clinical trials (REec), EudraCT code: 2017-001303-77. Results: Twelve subjects were recruited. Different patterns of rate and amount of the studied analytes are shown for oral and the several strengths of IV drugs tested. Ibuprofen, with an absolute oral bioavailability of 91%, showed an equivalent AUC of oral and IV administration. Tramadol showed an absolute oral bioavailability of 80%. Conclusions: Intravenous administration of Tramadol produces higher bioavailability (Cmax and AUClast) of the parent drug and lower of M1, than oral route. Dose normalized Cmax and AUClast of Tramadol and M1 were into the bioequivalence interval. Upon our pharmacokinetics study results, the intravenous dose of Tramadol should not be reduced when switching from oral dosing. No significant differences attributable to sex, once corrected by weight, were found.

Background: Paediatric patients are especially prone to experiencing adverse drug reactions (ADRs), and the surgical environment gathers many conditions for such reactions to occur. Additionally, little information exists in the literature on ADRs in the paediatric surgical population. We aimed to quantify the ADR frequency in this population, and to investigate the characteristics and risk factors associated with ADR development. Methods: A prospective observational study was conducted in a cohort of 311 paediatric patients, aged 1–16 years, admitted for surgery at a tertiary referral hospital in Spain (2019–2021). Incidence rates were used to assess ADR frequency. Odds ratios (ORs) were calculated to evaluate the influence of potential risk factors on ADR development. Results: Distinct ADRs (103) were detected in 80 patients (25.7%). The most frequent being hypotension (N = 32; 35%), nausea (N = 16; 15.5%), and emergence delirium (N = 16; 15.5%). Most ADRs occurred because of drug-drug interactions. The combination of sevoflurane and fentanyl was responsible for most of these events (N = 32; 31.1%). The variable most robustly associated to ADR development, was the number of off-label drugs prescribed per patient (OR = 2.99; 95% CI 1.73 to 5.16), followed by the number of drugs prescribed per patient (OR = 1.26, 95% CI 1.13 to 1.41), and older age (OR = 1.26, 95% CI 1.07 to 1.49). The severity of ADRs was assessed according to the criteria of Venulet and the Spanish Pharmacovigilance System. According to both methods, only four ADRs (3.9%) were considered serious. Conclusions: ADRs have a high incidence rate in the paediatric surgical population. The off-label use of drugs is a key risk factor for ADRs development.

According to the Ibuprofen Product‐Specific Bioequivalence Guidance of the European Medicines Agency, achiral bioanalytical methods are considered acceptable for demonstration of bioequivalence of ibuprofen‐containing products.The aim of this investigation is to compare the bioequivalence outcomes obtained with individual R and S ibuprofen enantiomers and the sum of both enantiomers from bioequivalence studies in which new intravenous ibuprofen products were compared with oral ibuprofen products. Bioequivalence was assessed for S and R enantiomers of ibuprofen and the sum of both enantiomers, which was calculated to represent the results that would have been obtained with an achiral assay. The infusion rates of 15, 20, and 30 minutes modify the maximum concentration (C_max) of the intravenous administrations. In contrast, the time when the maximum concentration is observed (T_max) was insensitive to detect differences in input rate within this range of infusion times. The eutomer S‐ibuprofen is the least sensitive analyte to detect differences in input rate; therefore, the regulatory acceptance of achiral bioanalytical methods for ibuprofen bioequivalence studies is justified because the sum of both enantiomers is more discriminative than the chiral methods where only the eutomer is used for regulatory decisions.