Pharmacokinetics and tolerability of meloxicam after i.m. administration

Transcription

1 Br J Clin Pharmacol 1996; 41: Pharmacokinetics and tolerability of meloxicam after i.m. administration H. NARJES, D. TURCK, U. BUSCH, G. HEINZEL & G. NEHMIZ Human Pharmacology Centre and Department of Pharmacokinetics and Drug Metabolism, Dr Karl Thomae GmbH, D Biberach an der Riss, Germany 1 The pharmacokinetics and tolerability of a new nonsteroidal anti-inflammatory drug (NSAID), meloxicam, administered i.m., were investigated in two studies conducted in healthy male volunteers. Study 1 was an open, placebo-controlled design in which 32 volunteers were randomized to a single ascending i.m. dose of meloxicam (5, 10, 20, and 30mg) or placebo. Study 2 had an open, randomized two way crossover design in which 12 volunteers received single i.m. and i.v. doses of meloxicam (15 mg). 2 Meloxicam showed an excellent tolerability in both studies. No effect was seen on serum creatinphosphokinase (CK, the isoenzyme of the skeletal muscle enzyme, CK-M M, was determined). 3 Following i.m. administration meloxicam was rapidly and completely absorbed (mean absolute bioavailability 102 %). Dose-proportionality was demonstrated with respect to C,,, (maximum plasma concentration) and AUC (extrapolated area under the plasma concentration-time curve from zero time to infinity) over a range of 5-30mg. 4 Intravenous administration of meloxicam (15 mg) resulted in higher initial plasma concentrations (C3min, i.e. concentration in plasma 3 min after start of injection = 2.99 f0.75 pg-ml-') than after ism. injection (Cmax: 1.62 f 0.20 mg ml-i). All other pharmacokinetic parameters were similar for both routes of administration (apparent elimination half-life = h; plasma clearance = 7-9 ml min- '). 5 In conclusion, the excellent tolerability of i.m. meloxicam together with its rapid and complete absorption may provide an alternative to oral administration of this drug. Keywords meloxicam tolerability pharmacokinetics i.m., i.v. Introduction Intramuscular (i.m.) administration of non-steroidal anti-inflammatory drugs (NSAIDs) is often used for rapid pain relief [ However, the i.m. route can be limited by local irritation and occasional necroses at the site of injection [4, 51. Therefore, the tolerability and pharmacokinetics of the i.m. route for administration of meloxicam. a new NSAID, was investigated in two studies conducted in healthy male volunteers. Animal studies of meloxicam have demonstrated good gastric tolerability in addition to marked antiinflammatory effects [6, 71 and data from clinical trials in rheumatoid arthritis and osteoarthritis indicate that meloxicam is both effective and well tolerated [8, 91. Like some other NSAIDs, meloxicam has been developed not only for oral administration, but also for i.m. use in clinical situations requiring rapid pain relief e.g. sciatica, lower back pain and acute flares of osteoarthritis. However, as most NSAIDs are poorly water soluble, it is important to ensure that absorption from the site of injection is complete. In addition, drugs intended for i.m. use should demonstrate good local tolerability. The aims of the two studies presented here were to determine the pharmacokinetics and tolerability of single i.m. doses of meloxicam in healthy volunteers Correspondence: Dr H. Narjes, Human Pharmacology Centre, Dr. Karl Thomae GmbH, D Biberach an der Riss, Germany Blackwell Science Ltd 135

2 136 H. Narjes et al. and to compare the pharmacokinetic parameters following i.m. and i.v. administration. Methods Subjects and clinical procedures The first study was of parallel group, dose-escalating design, blinded for placebo or drug but open with respect to the dosage group. Thirty-two healthy male volunteers (aged years) with normal body weights (range kg) received single i.m. doses of 5, 10, 20, and 30 mg meloxicam or placebo. Six subjects were randomly assigned to each dosage level while two additional subjects in each group received placebo. In the second study, 12 volunteers (aged years; with normal body weights [range kg]) were studied on two occasions in an open, randomized, two-way crossover design. Each subject received single doses of meloxicam (15 mg) both i.m. and i.v. (injection given over I min), with a 2 week washout period between doses. Both studies received Local Ethics Committee approval and were performed in accordance with the revised Declaration of Helsinki. No alcohol or concomitant medications were allowed during the study and smoking was prohibited. All subjects received meloxicam in a fasted state and were given a standardized continental breakfast 1 h after dosing. All i.m. injections were administered in the outer upper quadrant of the right gluteal region. A single meloxicam formulation (batch 90205, 10 mg ml-') was used and different volumes injected: 0.5, 1.0, 1.5, 2.0, and 3.0 ml for the 5, 10, 15, 20, and 30 mg doses, respectively. Isotonic saline (volume identical to that of the active formulation) served as placebo. To maintain double-blindness, the physician evaluating the tolerability was different from the one administering the drug. Volunteers were unable to identify which injection they had received. Any damage of muscle tissue is expected to result in elevated serum creatinkinase (CK) activities. Creatinkinase exists in three isoenzymes. The isoenzyme CK-BB which occurs in the brain, was presupposed to be negligible, the isoenzyme CK-MB (normal range I 10 u 1-') is selective for the myocardial muscle. The remaining isoenzyme CK-MM (normal range u I-') is selective for the skeletal muscle and was calculated as the difference between total CK and CK-MB as a indicator of muscle damage elicited by the injected drug. In the dose escalating study (study 1) CK-MM was determined predose and 3, 6, 8, 24, 48 and 96h postdose. The 96 h postdose sample was omitted after the 5 and 10 mg dosage, also the 48 h sample after the 5mg dosage. In study 2, which compared i.m. and i.v. administration, the CK enzyme activities were determined predose as well as 3, 8 and 24 h postdose. Symtoms indicating an inflammatory reaction (reddening, swelling, heat, spontaneous pain and pain on pressure) were recorded and evaluated using a four step scale. Blood samples (5 ml) were drawn via an indwelling catheter in the antecubital vein at 0, 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 32, and 48 h after all doses. 0.75, 72 and 96 h samples were also collected after i.m. doses of 15, 20, 30 mg and after i.v. dosing. Additional samples were withdrawn 1, 3, 5 and 10min after i.v. injection and 1.5 h after i.m. treatment. Blood was collected into heparinized tubes and the plasma separated by centrifugation and stored frozen at -20 C until analysis. Assay procedures Plasma concentrations of meloxicam were determined by high-performance liquid chromatography with on-line column-switching and ultraviolet detection. Plasma samples (50 pl) were applied to Bondapak@ C,, Corasil filled precolumns using sulphuric acid (0.01 M) and the precolumns were washed with the same eluent for 4min. The extract was then backflushed, using an eluent consisting of methanol/water/acetonitrile/glacial acetic acid (600/500/50/20 v/v) with 1.01 g heptanesulphonic acid, and chromatographic separation was achieved on a Hypersil@ ODS column (125 x 4.6 mm). Meloxicam was measured at 355 nm and evaluated using external standards. The assay was linear over the range 0.05 to 4.0pg m1-i. Plasma samples with concentrations higher than 4.0 pg ml-' were diluted prior to analysis. This method was validated and precision in quality controls samples (0.100, 0.750, 2.00 pg ml-') was within 7.4 YO ( YO, n = 9), assay accuracy was within 1.4 YO ( Yo, n=9). Data analysis Meloxicam plasma concentration-time data were analysed by standardized non-compartmental procedures [lo]. The maximum plasma concentration of meloxicam (C,,,) and the time to reach C, (tmax) were determined directly from the data. The elimination rate constant (h,) and the apparent elimination half-life (t+) were calculated by log-linear regression of the last four to eight drug plasma concentrations. The area under the plasma concentration-time curve (AUC (0, r)) was determined by the linear trapezoidal method and extrapolated to infinity (AUC). The mean residence time (MRT,,,) was calculated according to Gibaldi [ 101, and total plasma clearance (CL or CL/F) was obtained by dividing the dose by AUC. The absolute bioavailability of meloxicam after i.m. administration was obtained by dividing AUC,, by AUC,,. In order to evaluate the equivalence of these two routes of administration, bioequivalence criteria were applied to the log-transformed ratios of AUC. In the dose-escalating study, the samples size was taken as six per dose group (+two placebo subjects) in order to be sure of detecting potential frequent adverse events. In the comparative study, the aim was to obtain the differences between the mean values for the two Blackwell Science Ltd British Journal of Clinical Pharmacology 41,

3 I.m. injection of meloxicam 137 routes for AUC, t+ (h) and MRT,,,. Decision limits for stating equivalence of both treatments were set, which were analogous to those used in bioequivalence trials. The probability for detection of equivalence was derived from the expected variability of the data and was found to be equal to 0.9 with n= 12 subjects. Results Tolerability -- 4c L E 0) c $ C 2 a, 0 c 8 m 1 i m h O 'Time (h) The dose-escalating study showed that i.m. meloxicam was well tolerated. Only symptoms typical for an i.m. injection were reported (localized pain and pressure after injection): four volunteers reported these adverse events following placebo, no volunteer after 5 mg and two, two and four volunteers after meloxicam 10, 20, and 30 mg, respectively. Neither placebo nor meloxicam affected CK-MM values, whether analysed as an average change or evaluated as a maximal change from baseline. This is shown in Figure 1. Additionally, in the study comparing i.m. and i.v. administration, no increase in CK-MM levels was found. Pharmacokinetics The mean meloxicam plasma concentrations determined in the escalating dose (5-30 mg) study are shown in Figure 2 and the mean pharmacokinetic parameters are shown in Table 1. Ninety percent of the maximum meloxicam plasma concentration was achieved within min for all four doses. The elimination half-life, which ranged from h, was similar to values reported after oral administration [ 111. Both C,,, and AUC increased with increasing doses of meloxicam, with no apparent deviation from dose-proportionality in the range 5-30mg. This is demonstrated by the power model Y = a* doseb, where b was not significantly different from unity. The mean meloxicam plasma concentrations observed after i.m. and i.v. dosing (15 mg) are shown in Figure 3 L. 1 m -30 r g LC L 7-40 L-.i I I I I I I I / Time (h) Figure 1 CK-MM time course following 5( V ), 10( V), 20 (13) or 30 mg ( H) meloxicam or placebo (0) intramuscularly: Median changes from baseline, 32 subjects (eight on placebo, six on each dose of meloxicam). Figure 2 Mean meloxicam plasma concentrations following single i.m. doses of 5 (O), 10 (D), 20 (V) or 30 mg (0) meloxicam in groups of six healthy male volunteers (a total of 24). and the pharmacokinetic parameters are shown in Table 2. Pharmacokinetic data are given for 11 of the 12 subjects originally entered into the study, one subject inadvertantly receiving a perivenous administration of meloxicam. However, the perivenous injection was well tolerated, the subject did not experience any adverse events, including pain, and the plasma concentrationtime profile was similar to that observed after i.m. administration. As in the dose-escalating study, 90 YO of the maximum meloxicam plasma concentration was attained after 50 min. The mean maximum concentration (1.62i0.20 pg m1-i) was similar to that observed after a single oral dose of 30mg [ll]. Complete absorption was confirmed by a mean absolute bioavailability of 102 Yo. As expected, the i.v. administration resulted in higher initial meloxicam concentrations compared with the i.m. administration. However, both the i.m. and the i.v. plasma concentration-time curves (Figure 3) were superimposable within 1 h of dosing. Pharmacokinetic parameters were also very similar between i.m. and i.v. dosing (Table 2). Moreover, assessment of bioequivalence criteria revealed that the i.m. and i.v. routes were equivalent with respect to AUC. The 90 Yo confidence intervals ranged from YO for the ratio i.m./i.v. and were within the usual limits defined for equivalence with respect to extent of absorption. Results for dosenormalized C,,, (data not shown) and AUC following the i.m. dose corresponded to the values obtained in the dose-escalating study. Meloxicam was completely absorbed after i.m. dosing and showed no apparent deviation from doseproportionality with respect to both C,,, and AUC in a dose range of 5-30 mg. This is illustrated by the 95 YO confidence intervals of the parameter b of the power function which were O/O for C,,, and YO for AUC. Discussion Blackwell Science Ltd British Journal of Clinical Pharmacology 41, Intramuscular dosing may lead to a more rapid absorption of a drug in comparison with oral adminis-

4 ~~ ~~~~ ~ ~~ ~ 138 H. Narjes et al. Table 1 Pharmacokinetic parameters following single i.m. doses of 5, 10, 20. or 30 mg meloxicam in groups of six healthy male volunteers Meloxican 5 mg 10 mg 20 mg 30 mg Mean % cv Mean % cv Mean % cv Mean '55 CC' cmnx (Pg m1- I) tmnx (h) # t+ (h) AUC (pg h m1-i) MRTtot (h) CL/F(ml min-') NAUC (pg h ml-i mg-i) #: median and range. (NAUC: AUC values normalized to mg of dose).. - w """ Time (h) Figure 3 Mean meloxicam plasma concentrations following single i.m. (V) and i.v. (0) doses of 15 mg meloxicam to 11 healthy male volunteers. tration. This may be an advantage in the emergency treatment of pain. The results from both studies presented here showed that meloxicam was very well tolerated in healthy volunteers after i.m. and i.v. administration, with respect to local and systemic reactions. Intramuscular injections of NSAIDs are often accompanied by increased levels of serum CK, a marker enzyme for muscle damage [ 5, 121. Meloxicam in doses up to 30mg did not show any increase in CK-MM, indicating the absence of muscle tissue damage. The slight decrease in CK-MM values in some volunteers may be attributable to the avoidance of strenuous physical activity by the volunteers during the trial. The rarity of local reactions with meloxicam has also been confirmed by a study in patients with sciatica [data on file, Boehringer Ingelheim]. The pharmacokinetic parameters associated with i.m. dosing also indicate that this route of administration might provide a useful alternative to oral administration. Meloxicam was completely absorbed and showed no apparent deviation from dose-proportionality with respect to both C,,, and AUC over a dose range 5-30 mg. This statement is considered valid despite the fact that doses were not randomized and no crossover design was used. Consequently, the daily dose of meloxicam may be easily and rapidly adjusted according to the therapeutic needs of the patient. It is important to note that the mean maximum plasma concentration of meloxicam following i.m. administration of a single 15 mg dose was only about Table 2 Comparison of pharmacokinetic parameter values after a single i.v. bolus dose (15 mg) and a single i.m. dose. Confidence intervals are shown with lower and upper limits. The point estimator is given by exp(xi,m,/xi,v,), where Xi,m, and Xi.". are the means of the chosen pharmacokinetic parameter of the test and the reference preparation, respectively. Intravenous bolus Intramuscular *ConfirleriL P Mean % cv Mean % cv Ratio intervuls (90) Cmax (pg ml-') ' tmax (h) - - "1.5 " tt rh) AUC (pg ml- ' h) MRTto, (h) CL/F (ml min-') b NAUC (pg ml-' h mg-') (NAUC: AUC values normalized to mg of dose). ': concentration 3 min after i.v. bolus dose, b: CL/F in the case of i.m. injection, ': median and range, d: ANOVA CI (YO '%>) Blackwell Science Ltd British Journal of Chicid Phurmacology 41, I 39

5 I.m. injection of meloxicam 139 twice that observed after administering the same dose orally [ 111. Intravenous administration was associated with markedly higher initial concentrations (ratio i.v/p.o. 2.99/0.93), followed by a rapid decline. However, plasma concentration-time profiles from i.m. and i.v. doses were very similar after 1 h. After oral administration meloxicam achieves maximum concentrations 5-6 h post dose using once daily doses of 15 mg [ 111. More rapid attainment of higher plasma concentrations by i.v. or i.m. dosing may be an advantage for achieving a faster onset of action. Within approximately h of im. and i.v. administration of meloxicam, the plasma concentrations were similar to the steady state levels encountered during oral dosing (15 mg once daily). Therefore it is possible that analgesic therapy could be initiated with an i.m. or i.v. injection, followed by oral treatment. This would have the advantage that steady state concentrations could be achieved during the first day of therapy. An additional advantage may be that patients unable to swallow oral formulations can be treated. The authors would like to thank Mrs C. Huber for the excellent performance of analytical procedures and Mrs A. Holderried, A. Schuck and G. Franck for the excellent conduct of the trial. References 1 Wiseman KL, Kilgour M. Intramuscular piroxicam, a new drug dosage form, in the treatment of acute musculoskeletal disorders. J Znr Med Res 1985; 13: Nuutinen LS, Laitinen JO, Salomaki TE. A risk-benefit appraisal of injectable NSAIDs in the management of postoperative pain. Drug Safety 1993; 9: Dougados M, Listrat V, Duchesne L, Amor B. Comparative efficacy of ketoprofen related to the route of administration (intramuscular or per 0s). A double-blind study versus placebo in rheumatoid arthritis. Rev Rhum Ma/ Osteoartic 1992; Eandi M, Buraglio M, Casilli D, Grazia De Lucia M, Ruffilli MP. Injectable piroxicam in acute musculoskeieta1 disorder: Results of a multicenter study. Curr Ther Res 1989; 45: Vaccarino V, Sistori CR, Bufalino L. Local and systemic tolerability of piroxicam after intramuscular administration in healthy volunteers. Curr Ther Res 1989; Engelhardt G, Homma D, Schlegel K, Schnitzler Chr, Utzmann R. Anti-inflammatory, analgesic, antipyretic and related properties of meloxicam, a new nonsteroidal antiinflammatory agent with favourable gastrointestinal tolerance. Inflamm Res 1995; (in press). 7 Engelhardt G. Meloxicam. Potent inhibitor of adjuvantinduced arthritis in the rat. Scund J. Rheumatol 1994; 98 (Suppl.): 110, Abstract. 8 Lemmel EM, Bolten W, Burgos-Vargas R, et a/. A doubleblind placebo controlled study of 7.5 mg and 15 mg meloxicam in patients with rheumatoid arthritis. Scand J Rheumatol 1994; 98 (Suppl.): 111, Abstract. 9 Linden B, Distel M, Bluhmki E. Double-blind randomized comparison of meloxicam and piroxicam in patients with osteoarthritis (OA) of the hip. Scand J Rheumarol 1994; 98 (Suppl.): Gibaldi M. Biopharmaceutics and Clinical Pharmacokinetics. Lea & Febiger, 4th ed., Philadelphia, London, Turck D, Busch U, Heinzel G, Narjes, H. Effect of food on the pharmacokinetics of meloxicam after oral administration. CEin Drug Invest 1995; Michos N, Zulliger HW, Fenzl E. Pharmacokinetics and tolerability of suprofen. Experience with intramuscular application in healthy volunteers. Arzneim-Forsch 1985; 35: (Received 7 April 1995, accepted 9 October 1995) Blackwell Science Ltd British Journal of Clinical Pharmacology 41,