Pharmacokinetics of Tramadol in Human Neonates, Children and Adults and in Adult Rats, Cats, Dogs, Goats and Horses

Objective: To describe human maturation and between species differences in tramadol disposition.

Background: (+)-Tramadol (tramadol) and its phase I metabolite (+)-O-desmethyltramadol (M1) are weak µ-opioid receptor agonists that are structurally related to morphine. The O-demethylation of tramadol to M1, the main analgesic metabolite, is catalysed by CYP2D6. CYP2D6 polymorphisms have been shown to influence M1 production and the subsequent analgesic effect in humans. The pharmacokinetics of (±)-tramadol and (±)-M1 after intravenous administration have been investigated in several human studies as well as in dogs, goats, horses, cats and rats and extensive variability in disposition exists between species.

Methods: We have pooled data from twelve studies in order to construct an allometrically scaled pharmacokinetic model for (±)-tramadol and (±)-M1, and to explore the impact of size and age from neonate to adult in humans. 2469 serum (±)-tramadol and (±)-M1 samples were obtained, which included 56 human neonates and young infants (average postnatal age (PNA) of 2.6 weeks), 34 children (PNA 178.8 weeks), 41 adults (PNA 36.5 years), 6 adult dogs, 5 8-9 month old goats, 6 4-15 year old horses, 6 adult cats and 4 adult rats after intravenous administration of tramadol hydrochloride.

A two-compartment linear disposition model with zero-order input and first-order elimination was used to estimate clearance to (±)-M1 (CLPM1), tramadol clearance by other routes (CLPO), inter-compartmental clearance (QP), clearance of (±)-M1 (CLM), central volume (V1P), peripheral volume (V2P) and M1 volume (VM). Parameter estimation was performed using NONMEM (V6 2.0) with the first-order conditional interaction method. Parameter values were standardised to a body weight of 70 kg using an allometric model with scaling exponents 0.75 for CL and 1 for volume. Maturation of human clearances was described with postmenstrual age (PMA) using an empirical sigmoid model. Different assumptions were made to try to determine pathways of elimination.

Results: Adult human population parameter estimates (per 70 kg) were CLPM1 (extensive) 29.1 L h-1, CLM 77.5 L h-1, V1P 121 L, QP 27.2 L h-1, V2P 43.4 L, VM 1000 L (FIXED). CLPO was essentially zero in humans, cats and rats. The horse CLPO was 115 L h-1 per 70 kg with goat 39% and dog 22% of the horse. Human maturation of CLPM reached 50 % of adult values at 49.5 weeks PMA with a Hill coefficient of 5.0 while CLM matured at the same rate as glomerular filtration rate (50% at 47.7 weeks, Hill = 3.4). Slow metabolisers were detected in 3 % of the population with 11 % CLPM1 compared to extensive metabolisers.

Conclusions: Human tramadol elimination by CYP2D6 (CLPM1) matures 2 weeks later than (±)-M1 metabolite (CLM) elimination. Humans, cats and rats appear to eliminate tramadol almost exclusively by formation of the (±)-M1 metabolite while the horse, goat and dog appear to have extensive elimination by another route.