Over the last few months in this series I have examined the triumphs, intentional and otherwise, of industrial pharmacologists in the search for new and improved therapies for urological disease. Their undoubted skills, based on sound scientific principles, have been reinforced by the teaching of marketing manuals, wherein such concepts as ‘uroselectivity’ and ‘benign side-effect profile’ take on new meanings. Even allowing for this level of creativity it has become apparent that we may be reaching the limit to which drugs can be designed exclusively by targeting conventional receptors (e.g. α1-adrenoceptors and muscarinic receptors) or enzymes (e.g. phosphodiesterases). Equally, molecular biology has almost run its course in identifying new targets at either the gene or protein level. Should we consider therefore that we have reached the end of the road for target-organ selectivity?
In an attempt to address this issue, one can ask the following questions; (1a) are all α-blockers at the full ‘α-blocking dose’ equivalent? i.e. can one distinguish the difference between the conventional formulations of doxazosin, terazosin, alfuzosin and tamsulosin (0.8 mg)?; (1b) Are the clinical profiles of the antimuscarinics, oxybutynin, tolterodine, darifenacin and solifenacin similar?
In answer to these questions, although few direct comparative studies are available, it would appear that the committees of the International Consultations on Urological Diseases feel that in general all α-blockers and antimuscarinics are equal, and to paraphrase Karl Erik Andersson ‘any differences may be restricted to pharmacokinetic properties’. One can take Andersson's hypothesis a little further.
(2a) Is the clinical profile of doxazosin (CarduraTM) XL different from the original formulation of doxazosin and is the profile of oxybutynin (DitropanTM) immediate-release (IR) different from oxybutynin XL?
(2b) Is the clinical performance of tolterodine (Detrol™) different from that of tolterodine ‘long-acting’ and that of alfuzosin (Xatral™) IR different from that of alfuzosin sustained-release (SR).
At least for (2a), where several ‘gold standard’ comparative studies of bioequivalence, efficacy and tolerability have been conducted, there are obvious differences for doxazosin and oxybutynin. Although the clinical database is less complete, there are also several studies showing that the properties of IR and SR formulations of both tolterodine and alfuzosin have different clinical profiles.
In essence, what is analysed above is the impact of changing the pharmacokinetic profile of the drugs by re-formulation. This was first described for the gastrointestinal transport system (GITS) developed by Gupta at Alza Corporation (now part of Johnson and Johnson) which forms the basis of the XL technology incorporated in both Ditropan XL and Cardura XL. An analysis of the plasma drug profiles shows that the formulation slows the rate of absorption and extends the absorption period. In this way a much smoother plasma drug profile is obtained, with less evidence of ‘peaking’ and ‘troughing’. Not surprisingly for drugs with a good pharmacodynamic/pharmacokinetic relationship, an improved tolerability profile results. As higher doses can often be used as a result of improved tolerability, the efficacy is increased in these situations.
Similar absorption-modifying techniques have also been used in the development of both tolterodine and darifenacin, whereas the recently approved Watson product relies on an ‘external patch’ to improve the clinical profile, by altering first-pass metabolism of the active ingredient oxybutynin.
In general these pharmacokinetic manoeuvres will improve tolerability and perhaps, by increasing the therapeutic window, will result in some degree of improvement in efficacy. This can be exemplified with tamsulosin (FlomaxTM). Tamsulosin was originally developed in Japan as a conventional formulation, however, over the dose range evaluated (up to 0.2 mg) there was little sign of efficacy and there was a ‘ceiling effect’ caused by orthostasis. The version that is currently on the market is a controlled-release matrix formulation with a relatively slow absorption rate (6–8 h) that is effective while minimizing cardiovascular side-effects.
The impact of pharmacokinetic manipulation is not restricted to drugs that have been developed to treat LUTS associated with BPH and urinary urge incontinence. The development of a sublingual (SL) formulation of apomorphine has resulted in an acceptable therapy for erectile dysfunction (ED). The pro-erectogenic effects of the drug were originally found in Parkinson's patients being treated subcutaneously. As a result, oral preparations were evaluated first, but compliance was limited because of the inconsistent response (arising from low and variable bioavailability), as well as nausea and vomiting. The SL formulation appears to have circumvented these problems to a certain extent. Attempts are being made to refine the clinical profile of apomorphine further by the use of nasal delivery (NastechTM). It is projected that this will be of value in treating not only ED but also ‘female sexual dysfunction’. Several companies are developing nasal delivery forms for phosphodiesterase inhibitors for both male and female sexual health. Whether this is an attempt to improve on the clinical profile of sildenafil or bypass the Pfizer patents is unknown, but would seem equally foolhardy.
Target organ selectivity can also be achieved by specific delivery of the agent to a discrete anatomical area. In many ways this is analogous to the use of radioactive seeds in brachytherapy. Before sildenafil the local application (intracavernosal) of vasoactive agents was the most widely used treatment for ED and there are new cocktails, e.g. VIP/phentolamine (Invicorp, Senetek). Potentially, as we move into the era of gene therapy, intracavernosal administration of the gene constructs is likely to be the only viable option. The advent and departure of MUSETM would tend to suggest that intraurethral delivery is not a realistic option for treating ED.
Direct (intravesical) administration into the bladder is also relatively straightforward, and there has been some success in treating bladder dysfunction with capsaicin and resiniferatoxin (AfferonTM). There are several reports that the intravesical administration of oxybutynin is clinically more effective than systemic delivery, but equally the side-effects are increased.
Relatively recently, the injection of botulinum toxin into the musculature of the bladder has been shown by Chancellor and Fowler, among others, to be effective in the treatment of incontinence refractory to other forms of therapy. The successful clinical use of a relatively toxic agent certainly supports the need for further evaluations of localized drug delivery for, e.g. prostatitis and interstitial cystitis.
There has been considerable interest in the development of pro-drugs to circumvent pharmacokinetic (particularly low availability) issues and other factors. In urological drug development, fesoterodine (Schwarz Bioscience) is the furthest advanced of these. Fesoterodine is a pro-drug of the major metabolite of tolterodine. As the metabolite and parent drug have almost identical biological profiles, the clinical activity will be similar. The reaction of the tolterodine patent-holders (Pharmacia, and now Pfizer) is waited with much anticipation.
Finally, as we enter an era of combined therapy, an understanding of basic pharmacokinetic principles will become increasingly important in selecting the most appropriate treatment regimens.