Misba Beerahee, PhD(1) and Mark Sale, MD(2)
1)Clinical Pharmacology, Middlesex, UK and 2)Research Triangle Park, North Carolina USA. GlaxoWellcome Research and Development.
Excessive nitric oxide (NO) synthesis may be the critical link between the release of cellular mediators in the inflammatory cascade and pathological vascular smooth muscle relaxation in septic shock. Inhibition of nitric oxide synthase (NOS) activity could therefore be a useful method for managing the hypotension occurring in septic shock. Overproduction of NO may also contribute to other pathophysiologic features of septic shock such as myocardial depression, increased vascular permeability, lactic acidosis, and multiple organ dysfunction. 546C88 (also known as L-NG-methylarginine), a naturally occurring compound found at very low levels in human plasma, is a specific competitive inhibitor ofNOS. Exogenous administration of 546C88 may prove to be of benefit in reducing excess NO production, thereby reversing the pathological features of septic shock.
Prospective analysis was performed from sparse plasma data obtained in an international, multicenter, randomized (1:1), double-blind, placebo-controlled, dose-titration study in 312 patients over the intravenous infusion dose range of 5 to 20 mg/kg for 72 hours to compare the safety and efficacy of546C88 in patients with septic shock. Titration to higher doses was based on pre-defined haemodynamic profiles. A population pharmacokinetic- pharmacodynamic model was developed that simultaneously characterised the time course of drug exposure and pharmacological effect which takes into account placebo response. Influential patient covariates were also investigated.
A 2-compartment pharmacokinetic model with parallel first-order and Michaelis-Menten elimination which included simultaneous modeling of basal endogenous levels of 546C88 was used as the structural model. An indirect inhibitory response model integrating both treatment and placebo groups as well as accounting for competitive antagonism by an exogenous substrate was used to characterise the time course of plasma nitrate (end product of NOS inhibition) as a function of drug levels. Finally, a model was deemed necessary to characterise the haemodynamic (systemic vascular resistance) and physiological (oxygen extraction ratio) time profiles simultaneously for drug and placebo treatment groups. This was based on application of two parallel circuits, namely – ‘shunt’ resistance circuit which becomes significant in septic shock and the ‘physiological’ resistance circuit which tends towards normal. Operation of both circuits is modelled (linear/non-linear) as a function of withdrawal of three vasopressors (noradrenaline, dobutamine, dopamine), severity of disease at baseline and nitrate parameter estimates. The nitrate effect profile is in turn dependent on drug input and the exogenous competitive inhibitor, arginine.
Because of the complex multi-factorial clinical pathologies exhibited by septic shock, characterisation of the above PK-PD relationships is essential to model and to subsequently simulate the therapeutic outcome (resolution of shock) with 546C88.
Simulation of the developed models helped to
* provide expected exposure for phase III dosing regimens and bounds of variability using Monte-Carlo technique.
* characterise consequences on pharmacological effect of different dosing regimens of 546C88 over a range of dose levels.
* to evaluate the critical levels of the exogenous competitive inhibitor, arginine, likely to shift the concentration-response of 546C38 and make appropriate study design recommendations
Reference: PAGE 7 () Abstr 681 [www.page-meeting.org/?abstract=681]
Poster: oral presentation