Pharmacokinetics of Epanolol After Acute Andchronic Oral Dosing In

Br. J. clin. Pharmac. (1990), 29, 333-337

Pharmacokinetics of epanolol after acute and chronic oral dosing in elderly patients with stable angina pectoris

J. HOSIE', A. K. SCOPE2, J. C. PETRIE2 & I. D. COCKSHO1T3 'The Surgery, 1980 Great Western Road, Glasgow, G13 2SW, 2Clinical Pharmacology Unit, University of Aberdeen, Aberdeen Royal Infirmary, Foresterhill, Aberdeen, AB9 2ZB and 3Safety of Medicines Department, ICI Pharmaceuticals, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG

1 Epanolol is a novel anti-anginal agent which is a 1 1-adrenoceptor partial agonist exhibiting selective 1l-adrenoceptor antagonist and selective 1l-adrenoceptor agonist activity. It is mainly metabolised to conjugates prior to excretion in urine and it was of interest to determine if any accumulation occurred in elderly patients. 2 The pharmacokinetics of epanolol have been studied over 72 h after a single oral dose of 200 mg and then over 24 h after 12 consecutive daily oral doses in 13 elderly patients with stable angina pectoris. 3 The peak plasma concentrations (mean ± s.d.) after the single dose (25.7 ± 17.0 ng ml-) were not significantly different (P = 0.35) from those at steady state (32.4 ± 20.9 ng ml-'). There was wide inter-individual variation on both occasions. The time to peak did not alter significantly during the study with mean values of 1.5 and 1.2 h on acute and chronic dosing respectively. 4 Plasma concentrations declined biphasically with a mean terminal phase half-life of 17 h and 5 fold inter-individual variation. 5 The mean area under the curve to 24 h was not significantly different (P = 0.26) after the single dose (59.0 ± 29.8 ng ml-' h) from that at steady state (78.4 ± 55.0 ng ml-1 h). There was also wide inter-individual variation in these values. 6 In conclusion, the lack of significant accumulation of epanolol indicates that no alteration of dose is necessary when using epanolol in elderly patients with normal renal and hepatic function. Keywords epanolol pharmacokinetics elderly angina

Introduction Epanolol (Visacor, ICI 141,292) is a ,- and not significantly reduce cardiac output, blood adrenoceptor partial agonist, exhibiting selective pressure or peripheral blood flow. ,B-adrenoceptor antagonist and selective Pl- The partition coefficient, log P, of epanolol adrenoceptor agonist activity. The degree of between octanol and water is low (0.92) (Bilski agonism is approximately 20% of the full et al., 1988b) making it a relatively hydrophilic response seen with isoprenaline in the dog drug. It is mainly metabolised to conjugates model (Bilski et al., 1988a). The partial agonist prior to excretion in urine. However, renal activity (PAA) of epanolol at the 1 -adreno- clearance of unchanged drug constitutes about ceptor provides potential for clinical benefits in 25% of total clearance (Cockshott, 1989). The patients with angina as it may avoid bradycardia efficiency of renal clearance processes is known Correspondence: Dr J. Hosie, The Surgery, 1980 Great Western Road, Glasgow G13 2SW 333 334 J. Hosie et al. to decrease with age but the effect of age on The study size calculation was based on having conjugation in the liver has not been studied 95% power to detect an accumulation of the extensively. Many elderly patients suffer from drug of 50% or more. The main endpoint was angina and anti-anginal efficacy has been ex- the ratio of day 15 to day 1 AUC(24) and vari- amined specifically in this important group ability data from a previous study indicated a (Marlier, unpublished data). within patient variance of 0.185 for the AUC The aim of this study was to compare the ratio. The calculated requirement was 15 subjects pharmacokinetics of epanolol after single and but only 13 could be recruited. multiple doses and to ascertain whether there was any accumulation in plasma after 12 days of Heart and blood pressure administration. After resting supine for at least 5 min, heart rate was measured by palpation of the radial pulse Methods over 30 s and blood pressure by a standard mercury sphygmomanometer and arm cuff. Patient details Korotkoff phase V sounds were used for deter- mination of diastolic pressure. These measure- Thirteen patients (eleven males) were admitted ments were made on days 1 and 15 pre-dose, 2 h to the study. The mean age was 71 (range 65-77) and 24 h post-dose. years and the mean weight was 79 (range 56 to 105) kg. Creatinine clearances were calculated Drug analysis for nine of the patients and all were above 60 ml min- 1 and considered to indicate normal renal Blood was collected into oxalate tubes and function for subjects of these ages. All patients plasma separated and stored at -20° C until were considered to have normal hepatic and assayed using a radioimmunoassay technique. renal function as assessed by serum biochemical Anti epanolol antibody was raised in sheep to a markers. conjugate of epanolol with bovine serum albumin; the antibody was bound to magnetic Study design particles to aid separation of antibody-bound epanolol from unbound epanolol. [3H]-epanolol This was an open study in elderly patients with was prepared by the catalytic dehalogenation of stable angina pectoris. The study received local dibromo-epanolol using tritium gas; the specific ethics committee approval and was conducted in activity achieved was 23 Ci mmol-'. The speci- accordance with the Declaration of Helsinki. ficity of the RIA for epanolol was confirmed in All patients gave informed consent to participate each assay run by the inclusion of a sample of in the study. With the exception of short-acting pooled plasma from dosed patients. The concen- nitrates, all previous anti-anginal therapy was tration of epanolol in this sample had previously discontinued over 1 week prior to the first dose been determined by h.p.l.c. assay. Furthermore, on day 1. One patient was taking ferrous gluco- none ofthe known human metabolites of epanolol nate, one taking antacids and two taking thiazide cross-react significantly in the RIA. The limit of diuretics throughout the study. On day 1 patients detection of the assay (0.14 ng mlV 1) was defined received a single oral dose of 200 mg epanolol. as the response value which was significantly Blood samples were withdrawn before the dose below, with > 95% confidence, the mean and 15, 30, 45, 60, 90, 120, 180, 240, 480, 600, response of human plasma in the assay. The 720 min and 24, 32, 48, 56 and 72 h after the dose between batch coefficient of variation was 23% through an indwelling intravenous cannula for over the range ofconcentrations observed in this the first 12 h and by direct venepuncture there- study. All samples were assayed in duplicate, after. This was followed by once daily dosing with triplication or quadruplication where the difference between replicate results was > 10%; with 200 mg epanolol for 12 consecutive days caused this (days 4 to 15 inclusive). On day 15, blood samples this minimised any bias to the data by were collected before the dose and at 15, 30, 45, relatively high coefficient of variation. 60, 90, 120, 180, 240, 480, 600, 720 min and 24 h after the dose. Sampling was limited to 24 h on Pharmacokinetic calculations day 15 because this yields enough information to determine whether or not accumulation has The area under the plasma concentration-time occurred and improved the acceptability of the curve to 24 h (AUC(24)) was calculated using study in our elderly patients. the trapezoidal rule for both study days. Pharmacokinetics ofepanolol 335 An assessment of the accumulation of epanolol Wilcoxon's matched pairs signed rank test was over the dosing period was made by determin- used to compare the time to peak concentration ing, for each individual, an accumulation ratio (tmax) from each study day, in view of the (AUC(24) ratio) defined as: restricted scale of measurement. The exact probability was calculated using a randomisation AUC(24) day 15 test approach. AUC(24) day 1 AUC(oo) was calculated using the trapezoidal rule to the last detectable concentration and was Results extrapolated to infinity using the slope of the terminal elimination phase. The plasma elimina- Pharmacokinetics tion half-life (t½l,) was calculated from the slope of a log-linear regression ofthe terminal elimina- The log plasma-concentration-time curves on tion phase. day 1 and day 15 are shown in Figure 1 and The contribution of the pre-dose to the peak individual derived pharmacokinetic parameters concentration (Cmax) was assessed for each in- in Table 1. Epanolol plasma concentrations rose dividual by calculating the pre-dose/Cmax ratio rapidly to reach mean Cmax values of 15.7 and on day 15. 32.4 ng ml-' at 1.5 and 1.2 h for days 1 and 15 respectively. On about 25% of the sampling Statistical analysis occasions an analytically significant secondary peak was observed. On all these occasions both Inspection of plots for AUC(24) and Cmax on peaks occurred within 4 h of dosing. Plasma both study days indicated that logarithmically concentrations then declined biphasically with a transformed data were closer to a normal distri- mean (± s.d.) terminal half-life of 16.7 ± 8.6 h bution than untransformed data. Analyses were on day 1 (4.8 fold individual variability). No carried out on transformed data with natural accurate estimate of the terminal elimination logarithms being used throughout. Confidence half-life on day 15 could be obtained with the intervals (95%) were constructed for the differ- truncated sampling schedule employed on this ence between the means (on the logarithmic study day. Individual values of Cmax and scale) on days 1 and 15, based on paired t-tests. AUC(24) covered 5.7 to 13.4 fold ranges on both These confidence intervals and means were then sampling occasions (Table 1). back transformed to provide interval and point There was no significant difference between estimates (geometric mean ratios) for the ratios days 1 and 15 for any of the parameters measured. of the day 15 to the day 1 values of these variables. The geometric mean of the day 15/day 1 ratio for The hypotheses that the true ratios were 1: 1 Cmax was 1.23 (95% confidence intervals 0.78 to were tested. 1.94; P = 0.35) and for AUC(24) was 1.19 (C.I.

_ |2 ;~ : .. 1, e afte- $',...... o',e f ...... '

G" 3 6 .9 -218 21-j2~'27-30O 33 3863.942 4548

Figure 1 Mean (± s.d.) plasma concentrations of epanolol to 48 h post dosing. DayI ------Day 15. Epanolol could not be detected in plasma taken 72 h after the dose. 336 J. Hosie et al.

Table 1 Individual patient details and epanolol pharmacokinetic parameters Cmax AUC(24) A UC(oo) Age (ng ml-) tma.r (h) tJ Z (h) (ng ml-' h) (ng ml-' h) (years) Sex Day I Day 15 Day I Day IS Day I Day I DaylS Day 1 69 M 13.2 58.4 4.0 0.75 30.8 53.68 85.25 84.19 74 M 39.0 42.2 2.0 1.0 13.6 89.61 102.95 116.75 76 F 62.6 56.3 0.5 2.0 9.0 78.50 212.91 108.14 70 M 10.2 18.6 1.5 0.75 26.3 23.54 58.20 46.12 66 M 22.9 26.2 0.75 0.75 13.9 79.23 79.79 124.76 65 M 29.3 6.2 0.5 0.75 6.5 42.34 15.84 50.71 77 F 40.8 45.5 0.75 1.0 9.0 56.51 58.68 75.04 72 M 10.1 23.3 3.0 0.75 15.5 39.93 29.33 63.59 75 M 8.4 6.5 2.0 2.5 NC 34.68 28.94 NC 67 M 44.3 72.6 1.0 0.75 9.0 134.21 161.94 146.71 67 M 16.1 30.9 1.0 0.75 22.6 41.69 68.74 54.40 69 M 8.4 18.2 1.5 2.5 30.2 38.99 64.06 58.21 76 M 29.4 16.5 0.5 1.5 13.4 53.91 52.21 62.68 Mean 25.7 32.4 1.5 1.2 16.7 58.99 78.37 82.60 ± s.d. + 17.0 ± 20.9 ± 1.1 ± 0.7 ± 8.6 ±29.8 ± 55.0 ± 33.4 NC = Not calculable

0.86 to 1.63; P = 0.26)). The individual pre-dose atenolol and has subsequently been seen whilst concentrations on day 15 (0.9 ± 0.5 ng ml-') taking verapamil. were only 4 ± 3% of the corresponding Cmax values. AUC(oo) was 82.6 ± 33.4 ng ml-' h on day 1 Discussion with a 3.2-fold inter-individual variation. The pre-dose epanolol plasma concentration on Heart rate and blood pressure day 15 was only a small proportion of the corresponding Cmax value. This indicates that no The mean values of heart rate and blood pressure significant accumulation of epanolol occurs on on day 15 are given in Table 2. There was no administration of 12 consecutive daily doses to significant difference between Day 1 and Day 15 these elderly patients with angina. This observa- for any of these measurements. tion was also confirmed by the similarity of the Cmax and AUC(24) values on days 1 and 15. Safety No accurate estimate of the relative contribution of the two phases to the elimination of No patient withdrew from the study and only epanolol from plasma has been possible due to two minor adverse experiences were reported. the complex shape of many profiles. However, it One patient reported mild epigastric pain on day is clear from the lack of any significant 15 which had been occurring both prior to and accumulation, that the more rapid first phase throughout the study. Antacid treatment relieved must represent processes which play an impor- the condition. Another patient, on day 15, re- tant role in the clearance of epanolol from ported white fingers occurring on 2 days during plasma. the study. This had occurred previously on A secondary peak was observed in about 25%

Table 2 Resting heart rate and blood pressure (mean ± s.d.) recordings after single and chronic (12 days) dosing with epanolol. (Only nine patients provided these measurements consistently.) Day I Day 15 Heart rate (beats min-') 0 74 ± 11 68 ± 9 2 h 64 ± 5 70 ± 13 24 h 64 ± 5 69 ± 7 Blood pressure (mm Hg) 0 144/82 ± 20/11 139/80 ± 15/10 2 h 139/3 ± 19/11 144/76 ± 24/8 24 h 139/72 ± 14/8 127/74 ± 15/8 Pharmacokinetics ofepanolol 337 of the epanolol plasma concentration profiles. clearance (Cockshott, 1989). The known de- With such a short time difference (< 4 h) be- crease in renal function with age (Crooks & tween the two peaks it is unlikely that they are a Stevenson, 1979) would not, therefore, be ex- reflection of entero-hepatic re-circulation but pected to result in any appreciable change in the may be a consequence of two discrete sites for pharmacokinetics of epanolol with ageing. The absorption in the gastrointestinal tract as similarity of the Cmax and AUC(oo) data in this suggested for veralipride by Plusquellec et al. study with those reported for healthy young (1987). Another possible explanation has been volunteers (28.7 ng ml-' and 104 ng ml-' h put forward by Oberle & Admidon (1987) when respectively), given oral epanolol 200 mg with modelling cimetidine data. They suggested that food, are consistent with this prediction. variable gastric emptying rates combined with a No clinically significant fall in resting pulse short elimination half-life and poor gastric rate or blood pressure was recorded. Both mean absorption could be the cause of double peaks. resting heart rate and blood pressure fell on day The presence of double peaks in individual 1 but not on day 15. This apparent fall may be patients is unlikely to be of any clinical due to the relatively higher initial values on the significance. first presentation of the patients. This is in keep- The wide inter-subject variation observed in ing with the degree of partial agonist activity Cmax and AUC(24) values suggests a variable of epanolol and in contrast to the effect of bioavailability due to first pass metabolism and/ 13 1-adrenoceptor selective drugs without partial or differences in absorption. Pharmacokinetic agonism, such as atenolol. No drug-related data reported for epanolol in volunteers adverse effects were noted, though clearly a (Cockshott, 1989) indicate that it is subject to larger study is necessary to determine whether extensive first-pass metabolism with a low (8%) epanolol causes fewer adverse effects than bioavailability which was reduced by about 25% 1-adrenoceptor antagonists without partial when dosed with food. The observed variability agonist activity. in these elderly subjects with angina is similar to In conclusion, no alteration of dose is necessary that for other 3-adrenoceptor antagonists, when using epanolol in elderly patients with particularly those primarily cleared by metabolic normal renal and hepatic function. processes and therefore subject to first pass metabolism (Collett et al., 1981). The authors would like to thank Mrs A. T. Hunter, Mr The clearance of epanolol has been reported D. C. Jones, Mrs L. Field and Mrs S. M. Trumble for to be primarily hepatic with renal clearance plasma assays and Mrs P. A. Rollason and Miss Sue contributing only about 25% to the total body Oliphant for typing the manuscript.

References

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