Valle M, Drover D, Angst M, Verotta D.
Hydromorphone is a semi-synthetic opioid used in the treatment of moderate to severe pain. Its short elimination half-life makes it necessary to administer immediate-release (IR) formulations of the drug every 4 hours. As multiple daily dosing may result in decreased compliance, a new controlled-release formulation of hydromorphone (OROS) has been recently developed.
Aim: To model hydromorphone plasma concentrations after intravenous (IV), IR, and OROS administration using a semi-parametric approach.
Methods:
-Study dosing: 12 healthy subjects received: 8 mg dose in a 10 min IV infusion; 8 mg dose p.o. (IR); and 8,16, and 32 mg doses p.o. (OROS). Blood samples were drawn before and after the drug administration to determine hydromorphone plasma concentrations.
– Data analysis: The pharmacokinetics of hydromorphone were characterized using deconvolution: First , IV plasma concentrations vs. time data were deconvolved to estimate the IV disposition function (IV_H). Second, conditional on IV_H, IR and OROS dose, plasma concentrations vs. time data were deconvolved to estimate the unknown IR (IR_I) and OROS (OR_I) input rate functions. We used either a standard first order absorption model, or a constrained linear spline (semi-parametric model) to characterize these functions. For comparison, both individual and population analyses were carried out.
Results/Conclusions: IV disposition of hydromorphone was accurately described using a 3-compartmental model. The IR_I could not be described as a first order process because, as the semi-parametric model revealed, there is a fraction of drug following IR administration which is not immediately absorbed. The OR_I shows that the drug is absorbed over at least 24 hours, achieving the maximum absorption rate at approximately 10 hours, and decreasing progressively after this time. When the OROS data were deconvolved conditional on both IV_H and IR_I (incorrectly, because the IR_I shows some sustained release) the analysis misleadingly showed an apparent OROS non-linearity.
Reference: PAGE 9 () Abstr 106 [www.page-meeting.org/?abstract=106]
Poster: poster