Ketorolac tromethamine (ketorolac) is a non-steroidal anti-inflammatory drug (NSAID) used in the treatment of pain. The use of a sublingual analgesic has several advantages such as increased bioavailability and ease of administration, especially in patients who have difficulty swallowing.

FINANCIAL SUPPORTFINANCIAL SUPPORT

The aim of this study was to evaluate the pharmacokinetic profile of a formulation of ketorolac in Brazilian male volunteers.

DETERMINATION OF THE PHARMACOKINETIC PROFILE OF KETOROLAC TROMETHAMINE 30MG TABLET ADMINISTERED SUBLINGUAL ROUTE IN

HEALTHY VOLUNTEERS

DETERMINATION OF THE PHARMACOKINETIC PROFILE OF KETOROLAC TROMETHAMINE 30MG TABLET ADMINISTERED SUBLINGUAL ROUTE IN

HEALTHY VOLUNTEERS

Universidade Federal do Ceará – Departamento de Fisiologia e Farmacologia – Faculdade de Medicina Universidade Federal do Ceará – Departamento de Fisiologia e Farmacologia – Faculdade de Medicina

Unidade de Farmacologia Clínica – UNIFAC Unidade de Farmacologia Clínica – UNIFAC

Rua Coronel Nunes de Melo, 1127 - Rodolfo Teófilo, Cep: 60430-270 – Fortaleza, CERua Coronel Nunes de Melo, 1127 - Rodolfo Teófilo, Cep: 60430-270 – Fortaleza, CE

E-mail: cp.fisio@gmail.comE-mail: cp.fisio@gmail.com

PIMENTA COSTA, C.S.PIMENTA COSTA, C.S.; PONTES, A.V.; NASCIMENTO, D.F.; CAPISTRANO JUNIOR, V.L.M.; ROCHA, ; PONTES, A.V.; NASCIMENTO, D.F.; CAPISTRANO JUNIOR, V.L.M.; ROCHA,

M.B.S.; CUNHA, G.H.; MORAES, R.A.; FROTA BEZERRA, F.A.; MORAES, M.E.A.; MORAES, M.O.M.B.S.; CUNHA, G.H.; MORAES, R.A.; FROTA BEZERRA, F.A.; MORAES, M.E.A.; MORAES, M.O.

INTRODUCTIONINTRODUCTION

OBJECTIVESOBJECTIVES

METHODSMETHODS

This was an open, non-randomized, 01 period, 01 treatment, single dose under fasting conditions study where was administered 30 mg sublingual tablet formulation of ketorolac. Healthy Brazilians male were eligible for inclusion.

After an overnight fast, subjects received a single sublingual dose of the formulation. Plasma samples were obtained over a 24-hour period after administration. Plasma ketorolac concentrations were analyzed by High Performance Liquid Chromatography coupled Mass Spectrometry for analysis of pharmacokinetic properties, including Cmax, AUC0-24, and AUC0-∞.

The differences in pharmacokinetic parameters between the formulation of Ketorolac evaluated and studied by Galán-Herrera et al., 2008, probably due to:

Differences in bioanalytical technique: Mass Spectrometer x Ultraviolet DetectionNumber of blood collections for determination of plasma levels of Ketorolac: 18 x 13 collectionsBody mass of the volunteers: 74.4 ± 9.2 kg x 61 ± 8 kg

Pérez-Urizar et al., 2000, obtained the following parameters in a pharmacokinetic study of intramuscular administration in patients undergoing elective surgery:

Cmax was 3,27 ± 0,32 µg/mL, Tmax was 0,57 ± 0,06 hours and AUC0-24 was 9,45 ± 0,74 µg*h/mL

Pérez-Urizar et al., 2002, obtained the following parameters in a pharmacokinetic study of intramuscular or sublingual administration in 13 healthy women:

SL: Cmax was 2,44 ± 1,35 µg/mL, Tmax was 0,98 ± 0,12 hours and AUC de 11,89 ± 0,74 µg*h/mL IM: Cmax was 3,27 ± 0,17 µg/mL, Tmax was 0,46 ± 0,03 hours and AUC de 12,11 ± 1,19 µg*h/mL

We observed that significant differences in some pharmacokinetic parameters found when comparing the results of this as in other studies, could also be due to differences between the body masses of volunteers in this study and those found in the literature.

RESULTS AND DISCUSSION RESULTS AND DISCUSSION

Tolerability was assessed by vital sign monitoring, laboratory analysis results, anamnesis and physical examination. A total of 14 male subjects were enrolled and completed the study.

The pharmacokinetics parameters values calculated for formulation were as follows:

The most appropriate experimental design and applied in this study was open-ended, non-randomized, 01 period, 01 treatment, a single dose under fasting conditions.

A single dose is the regimen of choice for studies of bioequivalence and pharmacokinetic studies since it favors the detection of differences in the absorption process of the pharmaceutical forms used in addition to being safer for volunteers, have been less costly and requires less time for the test.

The collection time of the study were based on the elimination half-life of the drug as well as the predicted Cmax and Tmax.

The results of this study were similar to those observed in the literature, as following:

CONCLUSIONCONCLUSION

The bioanalytical method was successfully applied to analyze the pharmacokinetics of the tablet formulation of 30 mg of ketorolac tromethamine administered sublingually, and these parameters similar to those found in other formulations of ketorolac tromethamine.

The pharmacokinetic profile of sublingual formulation of ketorolac 30 mg is suitable for use in the frames of moderate to severe pain, especially in cases where the parenteral route is undesirable or unfeasible, or those who have difficulty swallowing. Moreover, it was demonstrated that the sublingual formulation provides security, since it was well tolerated at the dose administered and no adverse events were observed.

CNPq, CAPES, FUNCAP, FINEP, MS-RNPC-UNIFAC-HM, Instituto Claude Bernard.

Figure 2 - Mean plasma concentration curve versus time for the test and reference formulation of ketorolac 30mg tablet after single sublingual obtained by GALÁN-HERRERA et al., 2008.

Variável Unidade N Mean SD Min Median Max CV%

AUC%extrap (%) 14 3,37 1,02 1,83 3,32 4,98 30,31

AUC0-∞ ([ng*h]/mL) 14 9682 1908 6495 9550 12665 19.70

ASC0-24 ([ng*h]/mL) 14 9346 1789 6291 9305 12235 19.14

C24 ng*/mL 14 39.63 14.61 21.50 35.80 62.60 36.87

Cmax ng*/mL 14 2605 465 1780 2600 3270 17.85

Ke 1/h 14 0.12 0.02 0.1 0.12 0.16 12.79

t1/2 h 14 5.76 0.69 4.47 5.77 6.78 11.98

Tmax h 14 0.58 0.22 0.33 0.50 1.00 38.58

TABLE 1 - Values of descriptive statistics of the pharmacokinetic parameters obtained after single sublingual dose of ketorolac 30 mg (n=14).

FIGURE 1 - Plasma concentration curve of Ketorolac versus time after single sublingual administration in 14 healthy male volunteers.

TABLE 2 - Values of descriptive statistics of the pharmacokinetic parameters obtained after single sublingual dose of ketorolac 30 mg (n=14).

Ketorolac Dose Corrected by Body Mass

  Body MassDose and route of

administrationDose/kg

Ketorolac studied 74.4 ± 9.2 kg 30 mg sublingual 0.403 mg/kg

PÉREZ-URIZAR et al., 2002

59 ±2.2 kg30 mg sublingual

30 mg sublingual0.508 mg/kg

GALÁN-HERRERA et al., 2008

61±8 kg 30 mg sublingual 0.491 mg/kg

PÉREZ-URIZAR et al., 2000

64.9 ± 1.9 kg 30 mg intramuscular 0.462 mg/kg

ParametersFormulation 1 Formulation 2 Formulation 3

Mean SD Mean SD Mean SD

AUC0-∞ (µg*h/mL) 9,68 1,91 13,27 2,29 13,92 3,03

AUC0-24 (µg*h/mL) 9,35 1,79 11,80 2,20 12,17 2,60

Cmax (µg/mL) 2,61 0,47 3,44 1,02 3,61 0,90

Tmax (h) 0,58 0,22 0,94 0,81 0,66 0,38

T1/2 (h) 5,76 0,69 3,71 1,08 4,27 1,76

Formulation 1: Ketorolac studied; nº de volunteers= 14

Formulation 2: Ketorolac Reference; nº de volunteers = 26 (Galán-Herrera et al., 2008)

Formulation 3: Ketorolac Test ; nº de volunteers = 26 (Galán-Herrera et al., 2008)

TABLE 3 - Ketorolac dose corrected by body mass Ketorolac studied versus Pérez-Urizar et al., 2002; Galan-Herrera et al., 2008 and Pérez-Urizar et al., 2000.