Methods Find Exp Clin Pharmacol 2008, 30(1): 37-41
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2008 Prous Science, S.A.U. or its licensors CCC: 0379-0355/2008 DOI: 10.1358/mf.2008.30.1.1159648
Study of Paracetamol 1-g Oral Solution Bioavailability M. Farre´1, P.N. Roset1,2, S. Abanades1, E. Menoyo1, Y. Alvarez1, M. Rovira3 and A. Baena2 1
Unitat de Farmacologia, Institut Municipal d’Investigacio´ Me`dica (IMIM)—Hospital del Mar—Parc de Recerca Biome`dica de Barcelona (PRBB), Barcelona, Spain; Universitat Auto`noma de Barcelona, Barcelona, Spain; 2Laboratorios Gelos, S.L., Esplugues de Llobregat (Barcelona), Spain; 3MCC Analı´tica, S.A., Barcelona, Spain SUMMARY The aim of this work was to assess paracetamol bioavailability after administering 1 g in oral solution. Eighteen healthy volunteers were selected for this open-label study. A total of 15.4 ml of Gelocatil Oral Solution (Laboratorios Gelos, S.L.), corresponding to 1 g of paracetamol, were administered to fasting subjects. Blood samples were collected at 0 min, 10 min, 20 min, 30 min, 45 min, 1 h, 1.5 h, 2 h, 3 h, 4 h, 6 h, 8 h, 10 h and 12 h. Paracetamol plasma concentrations were determined by reverse-phase high-performance liquid chromatography. The study was conducted without deviations from protocol. Pharmacokinetic data from 18 subjects were allowed for estimating fast and high-paracetamol bioavailability: tmax 20 min (10–45) [median (range)], Cmax 24. 3 mg/l (6.5) [mean (standard deviation)], AUC0t 64.0 mg h/l (16.1) and AUC0–00 68.1 mg h/l (17.9). These results are comparable to those described for Gelocatil Oral Solution given at a 650 mg dose and for immediate release Gelocatil 650 mg tablets. Absorption speed was very fast, similar to that described for other oral-solution formulations, which provides an immediate onset of pain and fever relief. The results of this study show suitable bioavailability for 1 g Gelocatil Oral Solution, with fast-absorption speed that provides an immediate onset of pain and fever relief. ' 2008 Prous Science, S.A.U. or its licensors. All rights reserved.
Key words: Absorption - Bioavailability - Healthy volunteers - Paracetamol - Pharmacokinetics - Oral solution
INTRODUCTION Paracetamol is the analgesic of first choice for mild to moderate pain, both acute and chronic; it is also the first-choice antipyretic, both in children and in adults, as it shows similar efficacy to nonsteroidal antiinflammatory drugs (NSAIDs), but has a more favorable safety profile (1-4). Paracetamol is an inhibitor of prostaglandin synthesis but, unlike NSAIDs, it does not compete for the prostaglandin-synthetase cyclooxygenase site. Instead, it prevents prostaglandin-synthetase activation at the level of its peroxidase site, which occurs only under conditions of low-hydroperoxide levels. This dependence on peroxide levels explains its selective clinical behavior, which is fully manifested in the central mechanisms of fever or pain transmission, whereas lacks activity in the inflammatory process of peripheral tissues, platelets, gastric mucosa or in kidney function (5). Paracetamol’s unique action mechanism explains its outstanding gastrointestinal and renal tolerability and its lack of effects on platelet aggregation. In acute, shortterm treatment, paracetamol presents a frequency of adverse events similar to placebo, both in adults and in children. The few adverse events associated with its use make it particularly recommendable for the elderly
patients receiving several medications, and patients in whom NSAIDs are contraindicated. Paracetamol is also the analgesic–antipyretic of reference during pregnancy and lactation (6-11). Its maximum analgesic effect in adults is observed 0.5–2 h after administering a 0.5–1-g oral dose, and its effect may last up to 4–6 h. The recommended oral dose for the treatment of acute pain in adults is 500–650 mg every 4–6 h or 1 g every 6–8 h. In chronic pain, paracetamol up to 4 g/day is the recommended first-line analgesic, as it has shown the maximum efficacy and best safety profile in rheumatic and cancer pain patients (3, 4, 12-14). Paracetamol is rapidly absorbed in the proximal portion of the small intestine when orally administered, with a bioavailability of 80%–90%. Absorption speed depends mainly on the dissolution time of the pharmaceutical form and the gastric-emptying rate. When administered in solution form, under fasting conditions, and with an adequate volume of water, maximum paracetamol plasma concentrations may appear up to 15 min after administration. Paracetamol’s analgesic and antipyretic activity is closely related to its plasma concentrations, as paracetamol is rapidly distributed to its biophase, and pharmaceutical forms with a high-absorption speed
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M. Farre´ et al./Methods Find Exp Clin Pharmacol 2008, 30(1): 37-41
provide an early onset of the pharmacological effect. Additionally, it presents a low risk for pharmacokinetic interactions, and its pharmacokinetic profile is not modified by age or by coexisting chronic liver or cardiovascular conditions (1, 3, 15). In 1974, Gelocatil 650-mg tablets were the first paracetamol drug to be marketed in Spain (16). Subsequently, the range was extended to Gelocatil Oral Solution, a liquid form presented in bottles and in unit doses of 650 mg (10 ml), which showed its bioequivalence with the tablet form (17, 18). Both drugs stand out for paracetamol’s great absorption speed, leading to its short-latency effect time. The purpose of this study was to determine the bioavailability of paracetamol oral solution given at 1 g dose. SUBJECTS AND METHODS Subjects Eighteen healthy volunteers were selected according to the usual inclusion and exclusion criteria for these kind of studies: age, 18–45 years; weight: 50–100 kg; body mass index, 19–27 kg/m2; and a gender representation in the total sample of at least 40% for each one. A medical history was taken, and a physical exam, blood and urine analysis and electrocardiogram were performed on all of them. Female volunteers underwent pregnancy testing at the beginning and at the end of the trial, and also before administering the drug. Volunteers were informed verbally and in writing on the study objectives, procedures, requirements and risks, and they signed an informed consent form when they agreed to participate in the study. Study design The results presented derive from a relative bioavailability study between two different oral paracetamol formulations approved by the Comite´ E´tico de Investigacio´n Clı´nica (Clinical Research Ethics Committee) (no. 2003/1532) and later authorized by the Agencia Espan˜ola de Medicamentos y Productos Sanitarios (Spain Drug and Sanitary Products Agency) (03-0156). The clinical trial was conducted in June 2003, observing Helsinki’s international ethics declarations, deontology codes and the Spanish law, concerning clinical trials. The study consisted of an open-label clinical trial in healthy volunteers. Volunteers arrived at 8:00 AM following a 10-h fast and having not ingested water for at least 1 h; they received the drug around 9:00 AM, remained seated upright for at least 2 h after administration and were monitored for 12 h after drug administration. Volunteers had lunch and an afternoon snack 4 and 8 h after drug administration, respectively, and were not allowed to smoke until after eating.
Blood samples (10 ml) were collected through an IV catheter with safety lock immediately before (0 h), and 20 min, 30 min, 45 min, 1 h, 1,5 h, 2 h, 3 h, 4 h, 6 h, 8 h, 10 h and 12 h after drug administration. Blood was collected in heparinized vacuum tubes and mixed by inverting the tubes and centrifuged for 10 min at 3000 rpm at a temperature between 0 and 4 8C. Resulting plasma was separated into two aliquots in polypropylene tubes and stored frozen at 20 8C until its analysis. Paracetamol plasma concentration was determined following a validated method, through liquid–liquid extraction with ethyl acetate, reverse phase highperformance liquid chromatography (HPLC) and ultraviolet detector, using theobromine as the internal standard. The calibration line ranged from 0.2 to 40 mg/l, with a precision (variation coefficient of quality controls) of around 5% and an accuracy (relative error of quality controls) of around 10%. The quantification limit was established at 0.2 mg/l. The extraction recovery was around 75% for paracetamol and 50% for theobromine. Method selectivity was appropriate as well as sample stability during storage and analytical process. Vital signs (systolic and diastolic blood pressure, heart rate and oral temperature) were measured in the seated position with an automatic monitor immediately before drug administration (0 h) and 4 h and 12 h after drug administration. Subjects were questioned about potential adverse events before administration and after drug administration adverse events were recorded when subjects mentioned them spontaneously or when these became evident to investigators. Drugs Each subject received a single 1 g paracetamol dose in oral solution together with nonsparkling mineral water. Gelocatil Oral Solution, 15.4 ml (Batch S-004, expiration date July 2004, Laboratorios Gelos, S.L.) was administered with 224.6 ml of water. Pharmacokinetic analysis Standard pharmacokinetic parameters were calculated for each volunteer by means of a noncompartmental approach, using an in-house developed spreadsheet (Excel, Microsoft). The area under the curve (AUC0t) of the concentration with respect to time up to the last point with a quantifiable concentration (Ct) was calculated using the trapezoidal method. The elimination rate constant (ke) was estimated using log linear regression of concentrations in the terminal elimination phase, fitting the line that minimized the residual variance. Calculation of AUC to infinite (AUC0–00) was carried out by adding the Ct/ke ratio to AUC0t. Maximum concentration (Cmax) and time to maximum concentration (tmax) were derived from experimental data. Elimination half-life time (t1/2) was determined by calculating ln(2)/ke.
M. Farre´ et al./Methods Find Exp Clin Pharmacol 2008, 30(1): 37-41
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RESULTS Twenty-five (25) patients were screened to participate in the study, of whom one was excluded; six were kept in reserve and ultimately did not participate. The 18 subjects who completed the study were 8 women (44%) and 10 men (56%) with ages ranging from 20 to 37 years (mean 23), heights between 154 and 187 cm (mean 174 cm), weights between 53.8 and 80.6 kg (mean 66.6 kg) and body mass indexes within the limits established in the protocol. Six volunteers (33%) were smokers. Paracetamol plasma concentrations for each sampling time and the pharmacokinetic parameters derived from them are shown in Table 1, and the plasma concentration versus time curve is shown in Figure 1. Preadministration concentration values were lower than the quantification limit in all subjects. All subjects showed concentrations above the quantification limit, 10 min following administration, and after 12 h, they remained above the quantification limit. The administration of 1 g of paracetamol with Gelocatil Oral Solution produced an average maximum concentration of 24.3 mg/l in 20 min. Maximum concentrations were reached in 10 min in one volunteer (5%), in 20 min in nine volunteers (50%), in 30 min in five volunteers (28%) and in 45 min in three volunteers (17%). The estimation of the elimination constant included between three and four points in the terminal elimination line and was equivalent to a half-life time of 3.23 h. The area estimated with AUC0t was between 87 and 97% (average 94%) of the area estimated with AUC0–00. TABLE 1. Mean (n ¼ 18) paracetamol plasma concentrations and pharmacokinetic parameters, standard deviation (SD) and percentage of variation coefficient (CV%), following administration of Gelocatil 1-g Oral Solution (Laboratorios Gelos, S.L.). Time (h) 00 10 min 20 min 30 min 45 min 01 01.5 02 03 04 06 08 10 12 Cmax (mg/l) tmax (min) AUC0t (mg h/l) AUC000 (mg h/l) Cmax/AUC0t (h1) Ke (h1) t1/2 (h)
Mean
SD
CV%
BQL 14.22 19.94 20.00 16.72 14.84 12.14 10.37 7.64 5.94 3.31 1.98 1.28 0.84 24.33 20a 63.99 68.13 0.393 0.2208 3.23
– 10.91 8.38 4.68 3.95 3.97 3.43 2.71 2.10 1.77 1.29 0.66 0.54 0.36 6.48 10a 16.08 17.94 0.108 0.0351 0.61
– 77 42 23 24 27 28 26 28 30 39 33 43 43 27 45a 25 26 28 16 19
Median, minimum, and maximum for tmax. BQL, below the quantifiable limit (
