The effects of co-administration of benzhexol on the peripheral pharmacokinetics of oral levodopa in young volunteers

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1 Br J Clin Pharmacol 1996; 41: The effects of co-administration of benzhexol on the peripheral pharmacokinetics of oral levodopa in young volunteers J. ROBERTS, D. G. WALLER, A. G. RENWICK, N. O SHEA, B. S. MACKLIN & M. BULLING Clinical Pharmacology Group, University of Southampton, Biomedical Sciences Building, Southampton, UK 1 The effects of benzhexol on the absorption and pharmacokinetics of an oral dose of levodopa have been studied in 1 young healthy volunteers. Subjects were given a suspension of levodopa (25 mg) 9 min after either benzhexol (5 mg) or placebo in a randomized cross over design with doses separated by at least 1 week; on each occasion carbidopa was given 1 h before and 5 h after the dose of levodopa. Soluble paracetamol and radiolabelled DTPA were given with the levodopa as markers of gastric emptying. 2 Most subjects showed two peaks in the levodopa plasma concentration time curve on the placebo day, with the second minor peak occurring 1 2 h after the dose. After benzhexol administration all subjects showed two or more peak levodopa concentrations in plasma. Benzhexol administration caused a significant decrease in the maximum concentration (43%; P<.5) of the initial peak and an increase ( 22%; P<.1) in the maximum concentration of the second peak. This change in absorption profile caused by benzhexol significantly altered the ratios of the second peak compared with the initial peak for both the maximum concentrations (P<.2) and for the AUC values (P<.5). Benzhexol administration did not affect the total AUC of levodopa (7.3±1.9 vs 7.19±1.26 mg ml 1h; means±s.d.). 3 The plasma concentration time curves for paracetamol showed similar profiles to those for levodopa and the ratios of the peak concentrations and AUC values for the second peak compared with the initial peak were increased significantly by benzhexol administration (P<.5). The total AUC of paracetamol was not affected by benzhexol administration (39.4±8.2 vs 4.±8.9 mgml 1h; mean±s.d.) 4 Benzhexol altered the gastric emptying profile, shown by c-scintigraphy, with a reduced extent of initial emptying prior to the establishment of the plateau which is characteristic of levodopa administration in the fasting state. In consequence the ratio of the second to the initial phase of emptying was significantly higher (P<.1) following benzhexol treatment. 5 Benzhexol reduces the initial phase of gastric emptying after a dose of levodopa so that there is a decrease in the initial peak and a greater proportion of the dose is absorbed subsequently following the second phase of gastric emptying which occurs approximately 1 h later. Theoretically, this altered concentration time profile could be an advantage for some patients with Parkinson s disease. Keywords levodopa benzhexol gastric-emptying pharmacokinetics drug absorption Correspondence: Dr A. G. Renwick, Clinical Pharmacology Group, University of Southampton, Biomedical Sciences Building, Bassett Crescent East, Southampton SO16 7PX, UK Blackwell Science Ltd 331

2 332 J. Roberts et al. Introduction 72.5 (range ) kg, were studied. All gave written informed consent and the study was approved by the The rate of absorption of levodopa after oral adminislocal ethics committee and the Administration of tration is determined principally by the rate of gastric Radioactive Substances Advisory Committee. Subjects emptying [1]. Little levodopa is absorbed from the attended on two occasions separated by at least 1 week. stomach, and most undergoes active transport from the Subjects fasted overnight since dietary amino acids can small intestine via a specific uptake mechanism for large reduce levodopa absorption [ 7]. neutral amino acids. An unusual feature of levodopa In random order they were given either benzhexol pharmacokinetics is the frequent presence of more than (5 mg; Artane, Lederle Laboratories) or ascorbic acid one peak in the plasma concentration time curve (25 mg; as a placebo tablet) 9 min before receiving following a single oral dose. In young healthy volunteers, levodopa. Carbidopa, the peripheral dopa decarboxylase the liquid component of gastric emptying usually shows inhibitor, was given orally 1h before (1 mg) and a monophasic profile when assessed by gamma camera 5 h after (5 mg) the dose of levodopa. Just prior to the scintigraphy. Following an oral dose of levodopa, the dose of levodopa, subjects were positioned semiinitial rapid emptying is interrupted by a plateau phase recumbent on their back under a gamma camera with negligible emptying, followed by a second phase of (Siemens LFOV with 14 kev parallel hole collimator). rapid emptying [ 1]. In association with this pattern, Soluble paracetamol (1 g) and 99m-DTPA (diethylenetriseparate peak concentrations of levodopa are produced aminepentaacetic acid; 12 MBq), as pharmacological after each rapid emptying phase. Levodopa alters the and scintographic markers of gastric emptying, and gastric emptying profile in both young [1] and elderly levodopa (25 mg as a suspension) were given orally in [ 2] volunteers. Multiple plasma peaks are detected 1 ml water. when a single dose of levodopa is given in the fasting Gamma camera images of the gastric region of interest state [1, 2] and following a low protein meal [3] but were acquired every 6 s and imaging was continued are less common following a high protein meal [3]. until all the isotope appeared to have left the stomach. Rapid fluctuations in the clinical response to levodopa Blood samples (1 ml) were drawn through an indwellbecome increasingly common in patients with advanced ing forearm cannula immediately before and at 15, 3, Parkinson s disease. In some of these patients the 45, 6, 75, 9, 15, 12, 18, 24, 3, 36, 42 and effectiveness of levodopa is consistent only in the 48 min after levodopa was given. Plasma was stored at presence of a steady plasma drug concentration and 2 C until analysis. Paracetamol and levodopa were delayed or erratic gastric emptying may be an important measured as described previously [ 1, 6]. determinant of fluctuations in clinical response in some patients with Parkinson s disease [4]. In this situation the neuronal storage capacity for dopamine is believed Data analysis to be markedly reduced so that minute to minute delivery of levodopa may determine the extent to which Multiple peaks occur commonly in the plasma concensymptoms are relieved. The erratic and fluctuating tration time curve for levodopa following oral adminisplasma concentrations of levodopa produced by intertration. The concentration of the initial plasma peak of mittent delays in gastric emptying could therefore be levodopa or paracetamol (C ), the concentration of the detrimental. Fluctuations may be greatest with the first 1 second peak (C ) and the times of C and C (t and t ) dose of the day which is usually taken on an empty 2 are the observed values. The area under the plasma stomach. drug concentration-time curve (AUC) was calculated Anticholinergic drugs, such as benzhexol, are used in using the linear trapezoidal rule with extrapolation to the management of Parkinson s disease, often in combiinfinity; the terminal half-life was calculated by least nation with levodopa. The muscarinic receptor blockade squares regression analysis and the mean residence time produced by this class of drug is also believed to be from the AUC and the area under the first moment of responsible for their ability to inhibit gastric motility the plasma drug concentration-time curve (AUMC) as [ 5, 6]. The consequent delay in gastric emptying could described by Gibaldi & Perrier [8]. The paracetamol theoretically further affect the absorption of levodopa. and levodopa assays had coefficients of variations of The present study investigated the effect of approximately 5%. In the analysis of the plasma co-administration of the anticholinergic drug, benzhexol, concentration time curves for paracetamol and levoon the pattern of gastric emptying and absorption of dopa, a peak in the profile was defined as a rise in levodopa in healthy volunteers in order to define the concentration of at least 5% if it occurred in both extent of any drug interaction in the absence of ageing levodopa and paracetamol curves, or 1% if it was only and/or pathological changes likely to be present in present in one. patients with Parkinson s disease. The ratios of the peak concentrations for the second peak/first peak (C /C ) were calculated from the measured values. The ratios of the AUC values for the second peak/first peak were calculated by measuring Methods the AUC of the first peak as the (AUC + zero-trough Ten healthy male volunteers, with a mean age of 21 C /terminal slope) and the AUC of the second peak trough (range 2 22) years and with a mean body weight of was the (AUC AUC ). zero-infinity first peak

3 Benzhexol and levodopa absorption 333 Full details of the method of analysis of the scinti- levodopa (Figure 1) showed significantly lower concentrations graphic gastric emptying curves have been given elsewhere at early time points on the benzhexol day. The [1]. A plateau in the gastric emptying curve was curves crossed over at about h and significantly defined as a period with no gastric emptying for at least higher concentrations were detected at later time points 15 min. Measurements obtained from the curves were on the benzhexol day. the half-lives of the initial and final phases of emptying, The initial peak plasma levodopa concentration (C ) 1 the mean residence time for gastric contents (calculated was significantly reduced after benzhexol by a mean of from the AUC and AUMC of gastric radioactivity from 43% (P<.2) while the second peak (C ) although 2 the scintiscan) and the ratio of the decrease in gastric 22% higher after benzhexol was not significantly radioactivity in phase 2 compared with phase 1 (where different (Table 1). However, there was a significant three phases of emptying were recorded, the last two increase in the ratio of C /C (P<.2) and the ratio of were combined in this measure). the areas under the concentration-time curves for the The gastric emptying profiles were incomplete for two two peaks (AUC peak 2/AUC peak 1) (P<.5). The subjects who vomited about 1 2 min after the establishsment of a plateau phase of gastric emptying on the benzhexol but that to the second peak (t ) was 2 time to the first peak (t ) was increased slightly with 1 placebo day; in both cases the majority of gastric unchanged (Table 1). emptying occurred in the initial phase since the ratios There was no significant treatment related difference phase 2/phase 1 were.25 and.16. In consequence in the total AUC extrapolated to infinity despite the only the initial emptying half-life, and the ratio of phase greater proportion of the dose retained in the stomach 2/phase 1 emptying could be calculated from these data. Blood samples were collected normally for these subjects and the data are presented and discussed for treatment 6. related differences using data for all 1 subjects and also separately excluding (as appropriate) the data for the two subjects who vomited. Correlations were derived from linear least squares 5. analysis, and statistical comparisons performed using Student s t-test for paired data or the Mann Whitney U/Wilcoxon signed rank test; a P value of <.5 was taken as statistically significant. Results are expressed 4. as the mean±s.d. in the table and text and means±s.e.mean in figures. Results L evodopa pharmacokinetics On the placebo day seven subjects showed two peaks in the levodopa plasma concentration time curve; of the three subjects with a single levodopa peak, one 1. showed monophasic gastric emptying, one vomited and one showed a single levodopa peak despite a plateau on the gamma camera data (with about 25% retained) and a clear second peak of paracetamol coinciding with the end of the plateau. After benzhexol, nine Time (h) subjects had two peaks in the plasma levodopa concentration time curve and the other had three. The subject Figure 1 Plasma levodopa concentration-time curves for with three levodopa peaks also had three peaks of subjects given a suspension of levodopa with soluble paracetamol and two plateaux on the gamma scan. paracetamol and Tc-DTPA after pretreatment with Another subject with two plateaux on the gamma scan carbidopa and either placebo (solid circles) or benzhexol reached the end of the second plateau at a time when (open circles). The data are the mean values for 1 subjects blood sampling may have been too infrequent to detect with s.e.mean shown by bar lines. Statistically significant a third plasma drug peak so that only two peaks of treatment related differences (P<.5) were found by paired t-test at.25,.5,.75, 1, 4, 6 and 7 h and by signed rank test both levodopa and paracetamol were found. On the at.25,.5,.75, 1, 3, 4, 6 and 7 h. [Exclusion of the postbenzhexol day one subject showed a small secondary emesis data for the two subjects who vomited after 3 min (and possibly artefactual) increase (1%) in levodopa at and 5 min on the placebo day did not appreciably alter any a single time point which did not correspond to a of the mean concentrations (<8 ng/ml 1 difference); plateau on the gamma camera scan or a second peak in statistically significant differences (P<.5) were found by the paracetamol data. paired t-test at.25,.5,.7 and 1 h and by signed rank test The mean plasma concentration-time curves for at.25,.5,.7, 1, 1.5, 3, 4, 5, 6, 7 and 8 h]. Concentration (µg ml 1 ) 3. 2.

4 334 J. Roberts et al. Table 1 The effect of benzhexol on the absorption of levodopa and paracetamol when co-administered with Tc-DTPA L evodopa Paracetamol Placebo Benzhexol Mean of differences Placebo Benzhexol Mean of differences (95% CI ) (95% CI ) Number of subjects with two or more peaks C (mgml 1) ± ±2.29** 2.42 ( ) 17.4± ± ( ) t (min) 1 23 (15 3) 3 (15 3) 3 ( 5 +11) 15 (15 19) 23 (15 3) 8 ( +15) C (mgml 1) 2 2.2± ± ( ) 7.9± ± ( ) t (min) 2 9 (9 15)7 15 (9 19) 2 ( ) 9 (9 15)7 15 (9 15)9 15 ( ) Time to trough (min) 77±167 71±12 11 ( ) 75±157 63± ( 31 +1) AUC (mg ml 1h) 7.3± ± ( ) 39.4±.2 4.± ( ) Ratios C /C.63± ±1.24** 1.32 ( ).64± ±.85* 1.8 ( ) AUC /AUC.25± ±1.49* 1.51 (.1 3.1).3± ±1.18* 1.53 ( ) The results are the means±s.d., except for t and t which are given as the median and interquartile range, for subjects given levodopa, paracetamol and Tc-DTPA following the administration 1 2 of placebo or benzhexol. The results are for 1 subjects except where indicated by a superscript (see text for details). *P<.5, **P<.2 by signed rank test. C concentration of initial peak 1 C concentration of second peak 2 t time of C 1 1 t time of C 2 2 AUC area under the concentration-time curve extrapolated to infinity AUC /AUC ratio of AUC of second peak/auc of initial peak (see text)

5 on the benzhexol day. However, any difference may have been minimized because two subjects vomited on the placebo day. Exclusion of the data for these subjects gave levodopa AUC values of 7.51±.89 mg ml 1h on the placebo day and 7.17±1.3 mg ml 1 h on the benzhexol day; the slight difference was not statistically significant by either paired t-test or signed rank test. The plasma levodopa profiles correlated closely with the pattern of gastric emptying as determined by both the gamma camera data and the plasma paracetamol data. Paracetamol pharmacokinetics Concentration (µg ml 1 ) Benzhexol and levodopa absorption 335 After placebo, most of the plasma paracetamol concentration time curves showed profiles consistent with the 8 levodopa profile or the pattern of gastric emptying (see below). One subject had a single paracetamol peak 6 despite showing a plateau on the gastric scan and two levodopa peaks, but the second phase of gastric emptying represented only 15% of the total: a single paracetamol 4 peak was also found in one of the two subjects who vomited. One subject showed a second minor paracetamol 2 peak (8% increase) which coincided with a 17% increase in levodopa concentration despite an apparently single phase of gastric emptying by scintigraphy. After benzhexol pretreatment only one subject showed Time (h) an apparent discrepancy since secondary peaks of both Figure 2 Plasma paracetamol concentration-time curves for paracetamol and levodopa were detected while the subjects given soluble paracetamol with levodopa and gastric emptying profile showed a slow emptying over Tc-DTPA after pretreatment with carbidopa and either about 2 h, but without a clear plateau phase. placebo (solid circle) or benzhexol (open circles). The data The difference between treatments in the levodopa are the mean values for 1 subjects with s.e.mean shown by profiles (Figure 1) was reflected in the corresponding bar lines. Statistically significant treatment related differences mean plasma paracetamol concentration time curves (P<.5) were found by paired t-test at.5,.75, 1, 3, 4, 7 (Figure 2). The plasma paracetamol concentrations and 8 h and by signed rank test at.25,.5,.75, 1, 3, 4, 5, 6, (Figure 2) on the benzhexol day were significantly lower 7 and 8 h. [Exclusion of the post-emesis data for the two subjects who vomited after 3 and 5 min on the placebo up to 1 h, which corresponded to the initial period of day did not appreciably alter any of the mean concentrations gastric emptying. The mean concentration time curves (<.2 mg ml 1difference); statistically significant differences crossed over between 1.5 and 1.75 h after dosing and (P<.5) were found by paired t-test at.5,.75, 1 and 3 h were significantly higher on the benzhexol day at later and by signed rank test at.25,.5,.75, 1, 3, 4, 5, 6, 7, 8 h]. time points. The initial peak plasma concentration of paracetamol was lower after benzhexol pretreatment while the second had two distinct emptying phases separated by a peak was higher (Table 1) although, unlike for levodopa, plateau. After pre-treatment with benzhexol, one subject these differences did not reach statistical significance. who demonstrated a plateau after placebo had a rapid Consequences of this shift in absorption profile were monophasic emptying pattern; another subject had a that the ratios of C /C and AUC peak 2/AUC peak 1 prolonged slow initial emptying phase lasting 2 h, were significantly higher after benzhexol pretreatment followed by a late rapid emptying but no clear plateau; (P<.5) (Table 1). The time to the trough paracetamol of the other eight, six showed a single plateau while two concentration was slightly less on the benzhexol day had three phases of rapid emptying separated by two (Table 1) possibly in part due to the reduced amount plateaux. being absorbed in the first hour following the dose The gastric radioactivity (Figure 3) showed a similar (Figures 2 and 3). mean profile on each study day with a plateau between The differences in absorption profiles did not result about 2 3 min and 7 8 min after dosing. There was in any treatment related difference in AUC of paraceta- a smaller decrease prior to the plateau on the benzhexol mol calculated to infinity. day and in consequence, the gastric radioactivity was significantly higher between 15 and 5 min on the benzhexol day. Gastric emptying There were no significant differences between placebo On the placebo study day, two subjects had a rapid monophasic gastric emptying pattern, the other eight and benzhexol days in the initial emptying half-life (8±5 vs 26±36 min), the time to the end of the first plateau (77±1 vs 74±12 min), the final emptying

6 336 J. Roberts et al. % initial activity peaks (r=.7; P<.1) and the time of the second peak (t 2 )(r=.766; P<.5). Gastric emptying and paracetamol The ratio of the proportion of gastric emptying in phase 2/phase 1 correlated with the ratios for paracetamol of C /C 2 (r=.921; P<.1) and AUC peak2/auc peak 1 (r=.978; P<.1). The time to the end of the plateau on the scan correlated with the time to trough paracetamol concentration (r=.697; P<.1) and t 2 for paracetamol (r=.825; P<.5). Paracetamol and levodopa Correlations were found between various paracetamol and levodopa pharmacokinetic indices, ie t (r=o.765; P<.2), t (r=.769; 1 2 P<.1), time to trough plasma concentrations (r=.853; P<.1), C /C (r=.963; P<.1) and AUC peak2/auc peak1 (r=.985 P<.1) Time (h) Discussion Figure 3 Gastric emptying profile determined by gamma- camera imaging for subjects given radiolabelled Tc-DTPA with levodopa, carbidopa and paracetamol after pretreatment with placebo (solid circles) or benzhexol (open circles). The data are the means with s.e.mean shown by bar lines for 1 subjects of the percent of the initial radioactivity remaining in the stomach up to 2 h after dosing. There were statistically significant treatment related differences (P<.5) by paired t- test at 15 5 min and by signed rank test at min and 8, 95 and 1 min. Data collected on the two subjects who vomited on the placebo day are included to the last time point measured (3 and 1 min) There was a high incidence of multiple plasma levodopa peaks in this study. We have previously reported a lower number in young healthy volunteers [ 1] after 125 mg levodopa given with carbidopa, although the incidence was greater in elderly subjects [2]. Since the elderly achieve higher plasma levodopa concentrations than the young, the concentration of levodopa or one of its metabolites in the blood may be directly related to the production of gastric stasis. The greater incidence of multiple peaks in the young volunteers in the present study (in the absence of benzhexol ) may have been due to the higher dose of levodopa. The current study confirms the central role of gastric emptying in determining the peripheral pharmaco- kinetics of levodopa. This study also provides further support for the value of paracetamol as a marker of gastric emptying [6]. Correlations between indices derived from paracetamol plasma concentrations and levodopa pharmacokinetics provided similar infor- mation to that obtained from scintigraphy. There was a close relationship between parameters derived from half-life (12±9 vs 6±6 min) or the mean residence time of gastric contents (31±16 vs 41±19 min). However, the ratio of the proportion of gastric emptying in phase 2 compared with that in phase 1 was significantly plasma paracetamol concentrations and those from the greater after benzhexol (1.12±1.1) compared with scan, despite a loss of precision due to less frequent placebo (.26±.37) (P<.1 by signed rank test) data sampling with paracetamol. indicating a lower extent of gastric emptying prior to Benzhexol administration altered the pattern of gastric the plateau on the benzhexol day (mean of difference emptying produced by levodopa since it significantly (95% CI);.86 ( )). shortened the duration of the initial rapid emptying phase, leading to gastric stasis after less gastric emptying and therefore, at much lower plasma levodopa concentrations. As a result, the overall absorption of levodopa Correlations between gastric emptying, levodopa and paracetamol Gastric emptying and levodopa Close correlations were found between the proportion of gastric emptying in phase 2/phase 1 and the ratios for levodopa of peak concentrations C /C (r=.921; P<.1) and AUC peak 2/AUC peak 1 (r=.978; P<.1). The time to the end of the plateau on the scan correlated with both time to trough plasma levodopa concentration between was significantly slower and the initial peak plasma concentration was reduced, although the relative bioavailability of levodopa was unchanged. This could have important clinical consequences in those patients with Parkinson s disease who rely on high plasma levodopa concentrations to maintain a clinical response. Although the initial absorption of levodopa was reduced, the fluctuations in the plasma concentrations were smaller after benzhexol and this may be advantageous

7 Benzhexol and levodopa absorption 337 for patients who suffer from the on-off phenomenon emptying in healthy elderly volunteers. Eur J Clin Pharmacol in whom large variations in delivery of levodopa to 1992; 42: striatal neurons contributes to their disability. A small 3 Robertson DRC, Higginson I, Macklin BS, Renwick AG, study in six patients treated chronically with levodopa Waller DG, George, CF. The influence of protein containing meals on the pharmacokinetics of levodopa in healthy plus benserazide and the anticholinergic drug orphenadvolunteers. Br J Clin Pharmacol 1991; 31: rine, found delayed levodopa absorption in one and 4 Deleu D, Ebinger G, Michotte Y. Clinical and pharmacodecreased absorption in two patients; the authors kinetic comparison of oral and duodenal delivery of concluded that the chronic use of an anticholinergic levodopa/carbidopa in patients with Parkinson s disease agent may produce to a less predictable pattern of with a fluctuating response to levodopa. Eur J Clin levodopa absorption [9]. The data reported in healthy Pharmacol 1991; 41: young subjects in the present paper demonstrate a 5 Jaup BH, Stockbrugger RW, Dotevall G. Comparison clear but predictable effect of benzhexol on levodopa between the effects of pirenzepine and L-hyoscyamine in absorption. man. Scand J Gastroenterol 1982; 17: We conclude from this study that the addition of 6 Rashid MU, Bateman DN. Effect of intravenous atropine anticholinergic drugs to the therapy of patients with on gastric emptying, paracetamol absorption and heart rate in young and fit elderly volunteers. Br J Clin Pharmacol Parkinson s disease with levodopa could affect the 199; 3: profile of plasma levodopa concentrations. The change 7 Lennernas H, Nilsson D, Aquilonius SM, Akrenstedt O, in plasma profile is most likely to be of clinical relevance Knutson L, Paalzow K. The effect of L-leucine on the in patients who have advanced disease, particularly if absorption of levodopa, studied by regional jejunal perfusion they already show a fluctuating response to treatment. in man. Br J Clin Pharmacol 1993; 35: Gibaldi M, Perrier D. In Pharmacokinetics, New York: Marcel Dekker, References 9 Cortin M, Riva R, Martinelli P, Procaccianti G, Albani F, Baruzzi A. Combined levodopa-anticholinergic therapy in 1 Robertson DRC, Renwick AG, Wood ND, et al. The the treatment of Parkinson s disease. Clin Neuropharmacol influence of levodopa on gastric emptying in man. Br J Clin 1991; 14: Pharmacol 199; 29: Robertson DRC, Renwick AG, Macklin B, Jones S, Waller (Received 2 July 1995, DG, George CF. The influence of levodopa on gastric accepted 2 December 1995)