Encainide disposition in patients with

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Encainide disposition in patients with renal failure. Encainide, a benzanilide derivative, is a new antiar- rhythmic shown to be highly effective in the suppres-.
Encainide disposition in patients with renal failure The antiarrhythmic agent encainide undergoes extensive presystemic biotransformation to form 0-desmethylencainide (ODE) and 3-methoxy-ODE (MODE) in subjects who exhibit the extensive metabolizer (EM) phenotype for debrisoquin 4-hydroxylation. These metabolites contribute significantly to the overall antiarrhyttunic activity and are extensively excreted in the urine. Therefore, the effects of renal impairment on the disposition of encainide and its metabolites were studied in seven EM patients with renal failure and compared with those in eight healthy normal subjects of the same phenotype. After a single dose of encainide, its systemic and oral clearances were significantly lower and its elimination t112 was shorter in patients with renal failure than in healthy volunteers. This shortening was explained by a significant reduction in steady-state volume of distribution in renal failure. After chronic dosing to steady state, quantitatively similar changes were seen. Chronic oral dosing produced 80% higher levels of ODE (the most pharmacodynamically active metabolite) and 167% higher levels of MODE as compared with healthy volunteers. The prolongations in ECG intervals were similar in the two groups despite the higher encainide dose in the normal subjects. In conclusion, patients with renal failure will require lower doses of encainide because of both reduced encainide clearance and increased accumulation of active metabolites. (CLINT PHARMACOL THER 1986;40:64-70.)

Robert H. Bergstrand, M.D.,* Ted Wang, M.D.,** Dan M. Roden, M.D.,*** William J. Stone, M.D., Harold T. Wolfenden, Raymond L. Woosley, M.D., Ph.D., Grant R. Wilkinson, Ph.D., and Alastair J. J. Wood, M.D. Nashville, Tenn. Encainide, a benzanilide derivative, is a new antiarrhythmic shown to be highly effective in the suppression of ventricular ectopic depolarizations (VEDs)'-' and ventricular tachycardia.' However, like all antiarrhythmics, it may cause a worsening of ventricular arrhythmias in some patients." Chronic oral dosing of encainide prolongs conduction times throughout the conducting system, increasing both PR and QRS intervals, but produces only minor changes in QT intervals.39 From the Division of Clinical Pharmacology, Departments of Medicine and Pharmacology, Vanderbilt University School of Medicine and the Medical Service of the Nashville Veterans Administration Hospital. Supported by United States Public Health Service Grants No. GM 31304 and No. RR 0095 and by a grant from Mead Johnson Labs. Received for publication Oct. 1, 1985; accepted March 1, 1986. Reprint requests to: Dr. Alastair J. J. Wood, M.D., Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232. *Present address: Department of Medicine, University of Goteborg, Ostra Hospital, S-416 85 Goteborg, Sweden. **Present address: Department of Pharmacology, Tulane University School of Medicine, 1430 Tulane Ave., New Orleans, LA 70112. ***Recipient of the Clinician Scientist Award of the American Heart Association.

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In healthy volunteers encainide is virtually completely absorbed from the gastrointestinal tract and then undergoes a polymorphic pattern of biotransformation that co-segregates with the ability to oxidize the antihypertensive drug debrisoquin.10-12 This polymorphic pattern is characterized by two distinct phenotypes: extensive metabolizers (EMs) and poor metabolizers (PMs). In both the United Kingdom and North America, >90% of the white population is of the EM phenotype.'°-'s In the EM phenotype there is considerable presystemic metabolism, resulting in a systemic availability of only 30%, compared with 85% in PMs.14 In EMs encainide is metabolized to 0-desmethylencainide (ODE) and 3-methoxy-ODE (MODE), both of which have electrophysiologic activity.'''' Based on an individual's ability to 0-demethylate encainide, it is possible to determine that individual's phenotype:6 In dogs, ODE administered intravenously produces electrophysiologic effects similar to those produced by chronic administration of the parent drug.9"7 In addition to genetic constitution, disease states such as liver or renal disease's might affect the disposition of encainide. For example, in patients with liver disease the systemic and oral clearances of encainide were found to be significantly lower in cirrhosis, resulting in

VOLUME 40 NUMBER I

a threefold increase in oral bioavailability as compared with normal volunteers.' Encainide itself did not ac-

cumulate with chronic dosing either in the healthy volunteers or in the patients with cirrhosis, whereas the metabolites ODE and MODE accumulate in both groups to the same extent.' Our present study was designed to determine the effects of renal impairment on the disposition of encainide and its metabolites.

METHODS Patients. After approval of the Institutional Review Board and informed consent from the participants were obtained, seven men with severe renal failure (creatinine clearance 10 to 38 ml/min) who did not require dialysis were studied. Characteristics of the patients are listed in Table I. One patient developed frequent VEDs that began approximately 45 minutes after the first oral 50 mg dose of encainide and lasted for about 30 minutes. After this episode he was free from VEDs. This patient was not given any further encainide and was dropped from the study. All subsequent studies used half of the dose used in the normal subjects. The disposition of encainide in the six patients with renal impairment (mean age 45.8 years [range 31 to 56 years]; mean weight 71 kg [range 50 to 96 kg]) was compared with a group of eight healthy volunteers, who were studied in a similar fashion (mean age 30 years [range 24 to 40 years]; mean weight 71.1 kg [range 50 to 82.7 kg]) and whose data we have reported previ-

ously." Protocol design. The patients were admitted to the Vanderbilt University Clinical Research Center where they received their previously prescribed low-protein diet. Patients with hypertension continued their antihypertensive therapy (Table I) and cardiac rhythm was monitored continuously throughout the study. On day 1, after an overnight fast, approximately 0.4 mg (carbonyl) '4C-encainide HC1 was administered intravenously over a 10-minute period, followed by 50 mg unlabeled encainide HC1 by mouth. During the subsequent 48 hours, serial blood samples were drawn to be analyzed for encainide and its metabolites. Simultaneous with each blood sampling during the first 8 hours, vectorcardiography was performed for measurement of ECG intervals. Forty-eight hours after the initial dose, the patients received 25 mg unlabeled encainide HC1 by mouth every 8 hours for 2 days. After an overnight fast, on the third day of chronic oral dosing just before the seventh chronic oral dose of 25 mg encainide HC1, the patients were again given approximately 0.4 mg "Cencainide HC1 intravenously. Blood sampling and ECG

Encainide cirrhosis 65 studies were then performed over the subsequent 48 hours as described above. The normal subjects were previously studied according to a similar protocol,' except that they received a higher chronic dose of encainide HC1 (50 mg every 8 hours). ECG interval measurement. ECG intervals were measured from a vector cardiogram (Frank orthogonal leads) recorded at time periods corresponding to blood samples on a four-channel physiologic recorder with a paper speed of 100 mm/sec. R-R, PR, QRS, and QT intervals were measured visually and the mean of each interval was calculated from three to five consecutive complexes. Rate-corrected QT (QT) was calculated from the formula: QT. = QT/\/R-R. Interval changes were related to intervals measured on the morning of the first study day before drug administration. Pharmacokinetic analysis. On study days 1 and 5, 10 ml blood samples were drawn just before and 5, 10, 20, 30, 45, 60, and 90 minutes and 2, 3, 4, 6, 8, 11, 14, 24, 36, and 48 hours after both oral and intravenous drug administration via an indwelling cannula, kept patent by an isotonic dextrose infusion. The blood was placed into all-glass centrifuge tubes containing approximately 40 IU heparin, and the plasma was then separated and stored at 20° C until analyzed. The actual dose of radiolabeled encainide HC1 administered intravenously was calculated by weighing the syringe before and after the infusion. Radioactive and unlabeled encainide and its metabolites ODE, MODE, N-desmethylencainide (NDE), and N-O-didesmethylencainide (DDE) were determined by HPLC after extraction. The appropriate eluants were collected and counted by liquid scintillation counting as we have described:4 Subtraction of the contribution that the radioactive compound made to the total concentration provided the concentration of unlabeled drug. The plasma binding of "C-encainide (500 ng/ml) was determined in a prestudy sample by equilibrium dialysis for 3 hours.' Previous studies had shown encainide binding to be independent of concentration within the therapeutic range.' The pharmacokinetic parameters were calculated by standard methods. The elimination constant (1c) was calculated from the least-squares fit of the terminal portion of the log concentration-time plot, and the elimination t,/, was calculated as: ti,, 0.693/K. The plasma AUC values were determined by a combination of the linear and logarithmic trapezoidal methods.' Systemic clearance (CL) was calculated as: CL = Dose/AUC. The steady-state volume of distribution CL (AUMC/AUC). (V,$) was calculated as: Vs,

CLIN PHARMACOL THER

66 Bergstrand et al.

JULY 1986

Table I. Patient characteristics

Age

Serum creatinine (mg/dl)

BUN (mg/dl)

Measured creatinine clearance (ml/mm)

Serum albumin (gm/di)

Hypertension

Patient

(yr)lrace

Weight (kg)

A

51/B

50

5.1

36

12

3.8

No

B

31/B

61

11.9

85

10

4.8

Yes

C

56/W

77

6.8

46

20

2.7

Yes

D

48/B

67

4.4

25

15

4.3

Yes

E

47/B

96

3.8

26

38

4.2

Yes

F

42/W 47/AI

75

3.6 7.2

46

25 14

3.9 2.7

No

1

B

---

90

89

Yes

Black W = white; Al = American indian.

Table II. Pharmacokinetic parameters of encainide after intravenous administration in patients with renal failure and normal subjects after a single dose and after oral dosing for 3 days Single dose

Renal

failure (n = 6) Elimination t112 (hr) CL (L/min) CL0 (L/min)

1.7 ± 0.1 1.1 ± 0.1 2.7 ± 0.5

(L) Va (L) F (%) Plasma binding (%)

± 11 167 ± 15 45 ± 12

Vss

161

81 ±-

1

Normal subjects (n = 8) 2.7 ± 1.8 ± 12.4 ± 254 ±

0.3 0.2 4.3 24

397 -± 39 26 ± 7 70 ± 2

Multiple dosing

Renal

P