Population Pharmacokinetic-pharmacodynamic modeling of the Analgesic Effects of Lumiracoxib, a selective inhibitor of the enzyme COX2 in the Rat
Dalia A. Vásquez-Bahena (1), Uzziel E. Salazar-Morales (1), Mario I. Ortiz (2), Gilberto Castañeda-Hernández (1) and Iñaki F. Trocóniz (3).
(1) Sección Externa de Farmacología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Mexico city, Mexico; (2) Área Académica de Medicina del Instituto de Ciencias de la Salud, Universidad Autónoma del Estado de Hidalgo. Pachuca, Hidalgo. Mexico; (3) Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of Navarra, Pamplona 31080, Spain
Objectives: Lumiracoxib (LMX) is the most selective of the commercially available COX2 inhibitors (coxibs) [1]. Several coxibs have been withdrawn from the market due to unexpected side effects [2]. It has been pointed, that such withdrawals were due to insufficient information on the pharmacology of these drugs at the time of commercialization, and could be avoided if an adequate strategy, including pharmacokinetic-pharmacodynamic (PKPD) modeling, had been followed [3]. Therefore the objective of this study was to establish a PK/PD model for the analgesic effects of LMX in the rat, and characterize the in vivo concentration-response relationship of this drug.
Methods: Female Wistar (180-200 gr) rats received a subcutaneous injection of saline solution or carrageenan into the plantar surface of the right hind paw to induce inflammation and hyperalgesia. Experiment I: fasted rats received the carrageenan insult followed by oral administration of vehicle, 1, 3, 10 or 30mg/kg LMX dose. Plasma drug concentration was determined and the antihyperalgesic response was measured as the latency time (LT) to express a nociceptive behavior. Experiment II: rats were administered with vehicle, 10 or 30mg/kg oral dose of LMX at 4 h after carrageenan administration. The PK/PD modeling of the antinociceptive response was performed sequentially using a population approach (NONMEM VI).
Results: A two-compartment model described the plasma disposition of LMX. An input model, considering a lag time and a decrease of the relative bioavailability with the administered dose, was suitable to describe the absorption process. The response was predicted according with the following expression: LT(t)=LT0/(1+MEDt), where LT0 is the baseline response and MED represents the level of inflammatory mediators. The time course of MED was assumed be equal to the time course of COX2, calculated according with the formula: dCOX2/dt=kScox2(t)-kD_COX2xCOX2. The effect of LMX was considered by a reversible inhibition of the COX2 activity. The value of the in vivo estimate of the dissociation equilibrium constant (KD) of the COX2-LMX complex was 0.25 µg/mL.
Conclusions: The developed model was suitable to describe the time course of the pharmacological response of LMX according to its mechanism of action and its pharmacokinetics. PK/PD modeling thus is a useful tool to improve our understanding of the in vivo pharmacology of coxibs, and thus to optimize the therapeutic use of these agents.
References:
[1] Mysler E (2004) Lumiracoxib (Prexige®): a new selective COX-2 inhibitor. Int J Clin Pract 58:606-611.
[2] European Medicines Agency. Questions and answers on the recommendation to withdraw the marketing authorizations for lumiracoxib-containing medicines. London, European Medicines Agency, press realease, 13 December 2007. Doc Ref. EMEA/536363/2007.
[3] Hinz B and Brune K (2008) Can drug removals involving cyclooxygenase-2 inhibitors be avoided? A plea for human pharmacology. Trends Pharmacol Sci 29:391-7.
