Pharmacokinetic(s) matters: stroke treatment et cetera.

Abstract

Getting the right drug to the right place at the right time is crucial for therapeutic efficacy.This truism is well illustrated by the problem of ischaemic stroke. Stroke is the commonest cause of disability and the commonest cause of death following heart disease and cancer in developed countries. Interrupting the blood supply to an area of brain initiates a cascade of events including excitotoxicity, oedema and inflammation. Reperfusion can cause further damage. Such secondary processes occur relatively slowly (hours) offering hope for therapeutic intervention, but frustratingly the many neuroprotective drugs that have shown promise in animal models have been dismally negative in clinical trials (1). One novel approach to this problem relates to the naturally occurring interleukin-1 receptor antagonist IL-1RA, a 17 kDa protein that protects against ischaemic, excitotoxic and traumatic brain injury in rats. IL-1RA is available as a licensed intravenous (iv) preparation (anakinra) for treatment of rheumatoid arthritis in combination with methotrexate,although NICE does not recommend its use other than in controlled long-term clinical studies. Its safety (as an iv bolus followed by iv infusion) has been investigated in acute stroke patients in a phase 2 RCT (2): no serious adverse effects occurred and there was marked reduction in peripheral inflammatory markers. Gueorguieva and her colleagues (3) describe PK modelling of IL-1RA administered by iv bolus/infusion in plasma and cerebro-spinal fluid (CSF) of seven patients with subarachnoid haemorrhage. Modelling the data yielded rate constants of CSF entry and exit of 0.0019 h-1 and 0.1 h-1 respectively. CSF concentrations achieved were similar to the range that is effective in rats, but slow CSF penetration will probably result in subtherapeutic concentrations during the crucial early hours of an acute stroke using this regimen. If, as seems likely, brain tissue and thus CSF rather than plasma is the key compartment in this context, other therapeutic regimens (eg a larger bolus dose followed by a smaller maintenance infusion, or direct injection into CSF, or combination with drugs/measure(s) to impair the blood-brain barrier) may be needed to achieve therapeutic efficacy. It would be tragic if a large phase 3 study was initiated prematurely and ultimately gave a negative answer to the wrong question: the present small but critical study will be worth its weight in gold if it leads to an effective antistroke regimen in man and avoids this pitfall. Mazhar and colleagues used an entirely different pharmacokinetic approach to investigate deposition of salbutamol in its target site (small airways [lower order bronchi] of the lung), namely measurement of urinary salbutamol excretion in patients with exacerbations of asthma or of chronic obstructive pulmonary disease (COPD) (4). They applied this approach to compare lung deposition and systemic exposure by commonly used inhalation methods of administration used in hospital to treat acute exacerbations of asthma/ COPD. Relative lung deposition after inhaling 0.5 mg salbutamol from a metered dose inhaler with a spacer device was similar to 5 mg salbutamol from a sidestream jet nebulizer following acute exacerbation. Pharmacodynamic responses were similar, so the study highlights the comparability of these doses for each inhalation method evaluated with respect to lung deposition, systemic delivery and bronchodilator response.