L-dihydroxyphenylserine (Droxidopa) in the treatment of orthostatic hypotension

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1 Clin Auton Res (8) 8[Suppl ]:5 9 DOI.7/s z ARTICLE Christopher J. Mathias L-dihydroxyphenylserine (Droxidopa) in the treatment of orthostatic hypotension The European experience Received: 5 October 7 Accepted: 6 November 7 Prof. C.J. Mathias, DPhil, DSc, FRCP, FMedSci Neurovascular Medicine Unit Faculty of Medicine Imperial College London at St Mary s Hospital Praed Street London W NY, UK Tel.: +44-7/ Fax: +44-8/ c.mathias@imperial.ac.uk C.J. Mathias, DPhil, DSc, FRCP, FMedSci (&) Autonomic Unit National Hospital for Neurology and Neurosurgery Institute of Neurology University College London London, WCIN 3 BG, UK j Abstract Neurogenic orthostatic hypotension is a cardinal feature of generalised autonomic failure and commonly is the presenting sign in patients with primary autonomic failure. Orthostatic hypotension can result in considerable morbidity and even mortality and is a major management problem in disorders such as pure autonomic failure, multiple system atrophy and also in Parkinson s disease. Treatment is ideally two pronged, using non-pharmacological and pharmacological measures. Drug treatment ideally is aimed at restoring adequate amounts of the neurotransmitter noradrenaline. This often is not achievable because of damage to sympathetic nerve terminals, to autonomic ganglia or to central autonomic networks. An alternative is the use of sympathomimetics (that mimic the effects of noradrenaline, but are not identical to noradrenaline), in addition to other agents that target physiological mechanisms that contribute to blood pressure control. L-threo-dihydroxyphenyslerine (Droxidopa) is a pro-drug which has a structure similar to noradrenaline, but with a carboxyl group. It has no pressor effects in this form. It can be administered orally, unlike noradrenaline, and after absorption is converted by the enzyme dopa decarboxylase into noradrenaline thus increasing levels of the neurotransmitter which is identical to endogenous noradrenaline. Experience in Caucasians and in Europe is limited mainly to patients with dopamine beta hydroxylase deficiency. This review focuses on two studies performed in Europe, and provides information on its efficacy, tolerability and safety in patients with pure autonomic failure, multiple system atrophy and Parkinson s disease. It also addresses the issue of whether addition of dopa decarboxylase inhibitors, when combined with l-dopa in the treatment of the motor deficit in Parkinson s disease, impairs the pressor efficacy of Droxidopa. j Key words l-dihydroxyphenylserine Æ orthostatic hypotension Æ autonomic failure Æ noradrenaline Æ multiple system atrophy Æ Parkinson s disease CAR 5

2 6 Introduction Orthostatic (or postural) hypotension (OH) is a cardinal manifestation of generalised autonomic failure and often is the presenting feature in patients with primary autonomic failure due to pure autonomic failure (PAF) and multiple system atrophy (MSA) [9]. It is increasingly recognised also in Parkinson s disease []. It results in a number of symptoms, mainly as a result of hypoperfusion of organs, including the skeletal musculature. Organs above the level of the heart, such as the brain, are particularly susceptible to hypoperfusion; this can result in dizziness, visual disturbances, cognitive deficits and loss of consciousness [, 6]. Orthostatic hypotension can reduce mobility, result in falls, and may cause trauma and injuries, at times with devastating effects including death. The symptomatic consequences of OH, taken together can substantially reduce a patients quality of life. There are many causes of OH that can be considered under the mechanisms responsible - neurogenic, non-neurogenic and drug induced []. Non-neurogenic OH is rectified more readily than neurogenic OH, which often is difficult to treat, with management dependent on a combination of non-pharmacological measures and drugs [3, ]. A key factor in neurogenic OH is reduction in sympathetic nerve activity, and thus a reduction of the neurotransmitter, noradrenaline at the synaptic cleft. To replace this deficiency a variety of drugs that mimic noradrenaline have been used, that include ephedrine and midodrine, which are of partial benefit and have limitations to their use because of adverse effects. The ideal approach would be replacement of noradrenaline itself. L-threo-dihydroxyphenylserine (Droxidopa) has a structure which is similar to noradrenaline but with a carboxyl group. It can be administered orally, and is acted upon by the ubiquitous enzyme L-aromatic amino acid decarboxylase (dopa decarboxylase), which is found all over the body. It is converted directly to noradrenaline. It is likely to have both neuronal and extra neuronal effects, with a direct effect through noradrenaline on target organs. Droxidopa has been highly successful in replacing deficient or absent noradrenaline in patients with dopamine beta hydroxylase deficiency [4, 5, 5]. In Japan, it has been approved since 989 use for in the treatment of neurogenic OH due to various disorders, that include familial amyloid polyneuropathy, haemodialysis induced hypotension, and MSA and PD [8, 4, 6, 7, 8]. Experience with Droxidopa, especially in primary autonomic failure and PD in Caucasians is limited. Because of its potential value in the management of symptomatic orthostatic hypotension, two Phase II studies were performed in Europe. These were multicentre, multinational studies. An escalating dose of Droxidopa was used in the first study in patients with PAF and MSA. In the second a randomised double blind placebo controlled study was performed using three doses of Droxidopa in patients with MSA or PD. This review will describe key components from each of these studies, and will focus on whether inhibition of the enzyme dopa decarboxylase, which converts Droxidopa to noradrenaline, can influence its ability to reduce orthostatic hypotension. Droxidopa in pure autonomic failure and multiple system atrophy This study was performed in 6 PAF and 6 MSA patients with symptomatic orthostatic hypotension [7]. It was an open dose ranging study with a one week run in period, following which three doses of Droxidopa,, and 3 mg were administered twice daily. The incremental dose adjustment was dependent on the blood pressure response and an improvement in symptoms. When optimum dosage was reached the dosage was maintained for a 6 week period. The study therefore determined both the efficacy and the tolerability of increasing doses of Droxidopa in treating symptomatic orthostatic hypotension in PAF and MSA. This dose escalating trial was performed in ten centres within three countries in Europe. A key primary variable was to determine the extent of decrease in orthostatic fall in systolic blood pressure. Table provides details of the response to Droxidopa. The effects of Droxidopa persisted even at the last individual visit, with orthostatic systolic blood pressure reductions of, 9 and 3 mmhg respectively. In 5 patients (78%) OH had improved, and in 4 (44%) OH was not measurable. Importantly the mean supine systolic BP levels were not elevated (Table ). Thus Droxidopa, particularly in the highest doses, was efficacious in reducing OH (Fig. ). In this study, symptoms associated with orthostatic hypotension, that included light headedness, dizziness and blurred vision were assessed while on and when off Droxidopa drug. These were evaluated using bi-polar scales with ten point numeric objectivity. They showed an improvement in both objective and subjective evaluations of benefit (Fig. ). Droxidopa was well tolerated. There were two serious adverse events; laryngeal dyspnoea and syncope. The first was on mg twice daily and the second on 3 mg twice daily. Both could be attributed to the disease itself rather than to the drug. Supine hypertension was not reported.

3 7 Table Dose effects of L-threo-DOPS (Droxidopa) expressed as change from baseline, in multiple system and pure antonomic failure patients. L-threo-DOPS dose mg twice daily mg twice daily 3 mg twice daily Last individual visit per dose* n=3* n=5* n=7* Baseline orthostatic SBP decrease 54.3 ± ± ± 4.9 Final visit supine SBP.9 ± ± ± 3.9 Reduction in orthostatic SBP decrease )3. ± 8. )8.4 ± 54.4 ).7 ± 36.4 Reduction in orthostatic DBP decrease )9.4 ± 7. ).9 ± 3. ).5 ±.6 Noradrenaline while supine 56.5 ±,4. (n = 3) ±,4. (n = 3) 966. ± (n = 4) Noradrenaline at end of standing period,96.8 ±,8.8,35. ±,6.4,36.9 ± (n = 6) Last individual visit* n =7* n =8* n = 7* Baseline orthostatic SBP decrease 48.7 ± ±. 6.6 ± 4.9 Final visit supine SBP 9.3 ± ± ± 3.9 Reduction in orthostatic SBP decrease )9.7 ± 3.9 )8.5 ±. ).7 ± 36.4 Reduction in orthostatic DBP decrease )9. ± 8.8 )5. ± 8.6 ).5 ±.6 Noradrenaline while supine 47. ± ± (n = 7) 966. ± (n = 4) Noradrenaline at end of standing period,34.6 ±,77.5,33.5 ±,659.8,36.9 ± (n = 6) Analysis used all available data, with n values as shown in asterisked (*) rows unless otherwise specified against mean values. Orthostatic blood pressure decrease data were obtained after 5 min standing and are measured in mm Hg. Noradrenaline plasma concentration are pg/ml Data for noradrenaline at end of standing time represent actual values and are not presented as change from baseline SBP = systolic blood pressure; DBP = diastolic blood pressure From: Mathias CJ, Senard J-M, Braune S, Watson L, Aragishi A, Keeling J, Taylor M. L-threo-dihydroxphenylserine (L-threo-DOPS; droxidopa) in the management of neurogenic orthostatic hypotension: a multi-national, multi-centre, dose-ranging study in multiple system atrophy and pure autonomic failure. Clin Aut Res, ; In summary, Droxidopa was an effective drug which reduced the orthostatic fall in blood pressure in patients with PAF and MSA. It improved symptoms of OH and was well tolerated. It did not result in supine hypertension. The most effective of the three tested doses was 3 mg twice daily. Orthostatic BP fall at last visit (mmhg) Deterioration Improvement MSA Orthostatic BP fall at baseline (mmhg) Fig. Orthostatic systolic blood pressure decrease at baseline and at individual last visit. Individual orthostatic blood pressure decrease (mm Hg) after 5-minuties standing at last visit is plotted against decrease at baseline (all 3 efficacyevaluable patients). Each point below the line represents a patient whose condition improved between baseline and last visit, and every point above this line a patient whose condition deteriorated. From: Mathias CJ, Senard J-M, Braune S, Watson L, Aragishi A, Keeling J, Taylor M. L-threo-dihydroxphenylserine (Lthreo-DOPS; droxidopa) in the management of neurogenic orthostatic hypotension: a multi-national, multi-centre, dose-ranging study in multiple system atrophy and pure autonomic failure. Clin Aut Res, ; PAF Droxidopa in multiple system atrophy and in Parkinson s disease This study was designed to determine the minimum effective dose of Droxidopa that safely reduced the orthostatic fall in systolic blood pressure in comparison with placebo. After screening and evaluation a total of patients with either MSA or PD were randomized and received doses of,, 3 mg of Droxidopa or matching placebo. The drug was administered three times daily, as was placebo. It was conducted in 3 centres within 4 European countries. The screening period was between two seven days and the treatment continued for 8 days. Data was obtained in 55 patients with MSA and in 66 with Parkinson s disease. A preliminary report recently has been presented [3]. Droxidopa treatment resulted in a reduction in the orthostatic fall in blood pressure with each of the Droxidopa doses, unlike with placebo. It was noted that in the previous study the same patient had escalating doses with individual comparisons, unlike this second study with different individuals on different doses of drugs. There was no clear dose response improvement but the 3 mg dose was the

4 8 Fig. Transition table for the symptom Lightheadedness. Dizziness Analysis group: Overall, N = 3. ( = not at all, = very severe). Each * represents one patient (p =.5). From: Mathias CJ, Senard J-M, Braune S, Watson L, Aragishi A, Keeling J, Taylor M. L-threodihydroxphenylserine (L-threo-DOPS; droxidopa) in the management of neurogenic orthostatic hypotension: a multi-national, multi-centre, doseranging study in multiple system atrophy and pure autonomic failure. Clin Aut Res, ; Score after Treatment Baseline Score All Deterioration Improvement All most effective in reducing OH. Even with this dose mean levels of supine blood pressure were not elevated after acute or chronic dosage. The drug remained efficacious 8 days of treatment. In this study up to 9mg of Droxidopa was used each day, and adverse effects on heart rate were analysed. There was neither bradycardia nor tachycardia with any of the doses, at day or after 8 days of treatment. The majority of patients in this study had mild to moderate symptoms of dizziness, tiredness and visual disturbance. There was no loss of consciousness before or after drug or placebo treatment. There was an overall trend towards improvement in symptoms but this did not reach statistical significance. The reasons for the apparent dissociation between objective improvement in OH and subjective reduction in symptoms remains unclear. It may reflect the different individual characteristics of each group, or insensitivity of the symptom scales used. Droxidopa was well tolerated, with similar adverse effects in each of the treatment groups when compared with placebo. Most of the symptoms were mild. One patient had supine hypertension. In summary, therefore, 3 mg tid of Droxidopa was more effective than either or mg in the majority of patients with MSA or PD. It was well tolerated and with few side effects. Droxidopa in patients on dopa decarboxylase inhibitors Dopa decarboxylase is essential for the conversion of Droxidopa into noradrenaline and would be expected noradrenaline to reduce the formation of a dopa decarboxylase inhibitor and thus the prodrugs pressor effect. In each of the studies described there were patients treated with a combination of L-dopa and dopa decarboxylase inhibitors. In the first study these included MSA patients, and in the second both MSA and PD patients. There were no obvious differences in the beneficial response of Droxidopa in the first study with patients on a dopa decarboxylase inhibitor. Similar observations were made in the second study, where over 8% of the PD patients were on a dopa decarboxylase inhibitor. In a previous study in 4 PAF and MSA patients, pre-treatment with mg of the dopa decarboxylase inhibitor Carbidopa, prior to Droxidopa, blunted the pressor effects of Droxidopa []. Plasma noradrenaline levels rose from 94 ± 8 to 86 ± 35 pg/ml in Droxidopa treated patients compared to 6 ± 5 to 47 ± 7 after Droxidopa treated patients had been pretreated with Carbidopa, which thus attenuated, but did not abolish, the rise in levels of plasma noradrenaline. It is important to note that the dose of carbidopa used in this study [] was substantially higher than the dose used in clinical preparations when combined with l-dopa, these usually being 5mg for mg of l-dopa. In each of the European studies reported there was a beneficial pressor effect of Droxidopa despite the presence of a dopa decarboxylase inhibitor; this may reflect incomplete inhibition of dopa decarboxylase with the clinical preparations used to treat the motor deficits. The pressor effect may even have been higher without an inhibitor. Conclusions Treatment with Droxidopa, which results in the formation of noradrenaline, has been demonstrated

5 9 in two pan European studies to be effective, well tolerated and safe when used to treat orthostatic hypotension in patients with pure autonomic failure, multiple system atrophy, and Parkinson s disease. j Acknowledgements Major investigators have included Professor P Cortelli, Professor J M Senard, and many colleagues in participating centres. Disclosure Prof. C.J. Mathias was the Principal Investigator of both studies reviewed, which were supported by Sumitomo Pharmaceuticals, Japan. He is a Consultant for Chelsea Therapeutics, USA. References. Heims HC, Martin NH, Critchley HD, Jäger HR, Mathias CJ, Cipolotti L. (6). Cognitive functioning in orthostatic hypotension due to pure autonomic failure. Clin Aut Res 6:3. Kaufmann H, Saadia D, Voustianiouk A, Goldstein DS, Holmes C, Yahr MD, Nardin R, Freeman R. (3) Norepinephrine precursor therapy in neurogenic orthostatic hypotension. Circulation. 8: Lahrmann H, Cortelli, Hilz M, Mathias CJ, Struhal W, Tassinari M. (6) European Federation of Neurological Society guidelines on the diagnosis and management of orthostatic hypotension. Europ J Neurol 3: Man in t Veld AJ, Van den Meiracker AH, Boomsma F, Schalekamp MADH. (987) Effect of unnatural noradrenaline precursor on sympathetic control and orthostatic hypotension in dopamine beta-hydroxylase deficiency. Lancet ii: Mathias CJ, Bannister R, Cortelli P, Heslop K. Polak J, Raimbach SJ, Springall DB, Watson L. (99) Clinical autonomic and therapeutic observations in two siblings with postural hypotension and sympathetic failure due to an inability to synthesize noradrenaline from dopamine because of a deficiency of dopamine beta-hydroxylase. QJM, New Series 75(78): Mathias CJ, Mallipeddi R, Bleasdale- Barr K. (999) Symptoms associated with orthostatic hypotension in pure autonomic failure and multiple system atrophy. J Neurol 46(): Mathias CJ, Senard J-M, Braune S, Watson L, Aragishi A, Keeling J, Taylor M. () L-threo-dihydroxphenylserine (L-threo-DOPS; droxidopa) in the management of neurogenic orthostatic hypotension: a multi-national, multicentre, dose-ranging study in multiple system atrophy and pure autonomic failure. Clin Aut Res : Mathias CJ, Bannister R. () Dopamine beta-hydroxylase deficiency. In: Mathias CJ, Bannister R, (eds.) Autonomic failure. A textbook of clinical disorders of the autonomic nervous system. 4th ed. Oxford and New York: Oxford University Press pp Mathias CJ. (3) Autonomic diseases clinical features and laboratory evaluation. JNNP 74:3 4. Mathias CJ. (3) Autonomic diseases Management. JNNP 74:4 47. Mathias CJ. (5) Cardiovascular Autonomic Dysfunction in Parkinson s Disease and Parkinsonian Syndromes. In: Ebadi M, Pfeiffer RF. (Eds.) Parkinson s Disease. CRC Press LLC, New York Mathias CJ. (6) Orthostatic hypotension and orthostatic intolerance. In: DeGroot LJ, Jameson JL, de Kretser D, Grossman AB, Marshall JC, Melmed S, Potts JT, Weir GC. (Eds.) Endocrinology. 5th edition. Elsevier Saunders, Philadelphia PA, USA Mathias CJ, Senard JM, Cortelli P. (7) A double-blind, randomized, placebo-controlled study to determine the efficacy and safety of droxidopa in the treatment of orthostatic hypotension associated with multiple system atrophy or Parkinson s disease. Clin Aut Res 7:7. abstract 4. Narabayashi H, Nakanishi T. (987) Therapeutic effects of L-DOPS in Parkinson s disease, double-blind comparative study against placebo as control in patients with long-term levodopa therapy. Clin Eva 5: Robertson D, Goldberg MR, Onrot J, Hollister AS, Wiley R, Thompson JG, Robertson RM. (987) Isolated failure of autonomic noradrenergic neurotransmission. Evidence for impaired beta-hydroxylation of dopamine New Engl. J. Med 34: Sobue I, Senda Y, Hirayama K, et al. (987) Clinical pharmacological evaluation of L-threo-3-4-dihydroxyphenylserine (L-DOPS) in Shy-Drager s syndrome and its related diseases. A nationwide double-blind comparative study. Jpn J Clin Exp Med 4: Suzuki T, Higa S, Sakoda S, et al. (98) Pharmacokinetic studies of oral L- threo-3,4-dihydroxyphenylserine in normal subjects and patients with familial amyloid polyneuropathy. Eur J Clin Pharmacol 3: Yanagisawa N, Ikeda S, Hashimoto T, Hanyu N, Nakagawa S, Fujimori N, Ushiyama M. (998) Effects of L-threo- Dops on orthostatic hypotension in Parkinson s disease. No To Shinkei 5:57 63