Clinical Phannacokinetics 9: 26-41 (1984) 0312-5963/84/000 1-0026/$08.00/0 © ADIS Press Limited All rights reserved.
Clinical Pharmacokinetics of Verapamil Scott R. Hamann, Robert A. Blouin, and R.G. McAllister Jr Research Service, Veterans Administration Medical Center; the Graduate Center for Toxicology, the College of Pharmacy, and the Departments of Medicine and Pharmacology, University of Kentucky College of Medicine, Lexington
Summary
Verapamil is widely used in the treatment of supraventricular tachyarrhythmias as well as for hypertension and control of symptoms in angina pectoris. Unlike other calcium antagonists, detailed pharmacokinetic data are available for verapamil. Plasma concentrations of verapamil appear to correlate with both electrophysiological and haemodynamic activity after either intravenous or oral drug administration, although considerable intra- and intersubject variation has been found in the intensity ofpharmacological effects resulting at specific plasma drug levels. Verapamil is widely distributed throughout body tissues; animal studies suggest that drug distribution to target organs and tissues is different with parenteral administration from that found after oral administration. The dnlg is eliminated by hepatic metabolism. with excretion of inactive products in the urine and/or faeces. An N-demethylated metabolite, norverapamil, has been shown to have a/raction ofthe vasodilator effect ofthe parent compound in in vitro studies. After intravenous administration, the systemic clearance of verapamil appears to approach liver blood flow. The high hepatic extraction results in low systemic bioavailability (20%) after oral drug administration. Multicompartmental kinetics are observed after single doses; accumulation occurs during multiple-dose oral administration with an associated decrease in apparent oral clearance. Norverapamil plasma concentrations approximate those of verapamil following single or multiple oral doses of the parent drug. Because ofthe complex pharmacokinetics associated with multiple-dose administration and the variation in individual patient responsiveness to the drug, 'standard' dosing recommendations are difficult to determine; use of verapamil must be titrated to a clinical end-point. Further, the potential for alteration in verapamil's disposition by the presence of hepatic dysfunction or cardiovascular disorders which result in altered hepatic blood /low is only now becoming apparent. A potentially toxic interaction has been reported between verapamil and digoxin, in which renal excretion of the glycoside is impaired, but the true clinical significance of this remains debatable. Combination therapy with verapamil and /i-adrenoceptor blocking compounds has been advocated by some investigators, but may be hazardous because of the additive negative inotropic and chronotropic effects inherent in both agents.
Clinical Pharmacokinetics of Verapamil
Verapamil is a calcium channel blocking drug (Fleckenstein, 1977) which is widely used as an antiarrhythmic agent to control supraventricular tachyarrhythmias (Krikler and Spurrel, 1974; Singh et a!., 1980). The potent vasodilator and negative inotropic properties of verapamil also make it useful in the treatment of hypertension, ischaemic heart disease, and hypertrophic cardiomyopathy (Anakevar et aI., 1981; Gould et aI., 1982; Lewis et a!., 1978; Singh et aI., 1978; Woodcock et aI., 1980). Verapamil is currently available as a racemic mixture containing the D( -) and L( +) optical isomers. For the group of calcium antagonist drugs now in clinical use, pharmacokinetic and pharmacodynamic studies have lagged well behind clinical application, and reviews concerning the pharmacological characteristics as well as therapeutic potential of these compounds have only recently appeared (Braunwald, 1982; Ellrodt et aI., 1980; Leonard and Tolbert, 1982; McAllister, 1982). Verapamil was the first of the 'slow channel' blocking agents to find widespread clinical use, and it is the only drug of this group for which detailed pharmacokinetic data are yet available. This review includes the following: a critical evaluation of pharmacokinetic data obtained from verapamil administration to normal subjects, subjects with various disease states, and pertinent animal models; a review of evidence for a verapamil plasma concentration-pharmacological response relationship; a discussion of clinically important drug interactions involving verapamil; and consideration of pharmacodynamic data relevant to therapeutic drug monitoring.
1. Analytical Methods A major problem in the interpretation of pharmacokinetic studies with verapamil involves the various analytical techniques which have been used to quantitate parent drug and metabolite concentrations in plasma. A simple spectrophotofluorometric method (McAllister and Howell, 1976) has been used to characterise the pharmacokinetic properties of verapamil in dogs (McAllister et aI.,
27
1977) and in man (Koike et aI., 1979). Although this assay procedure is apparently useful in studies concerned with drug plasma concentrations following intravenous administration, fluorescent methods are unsatisfactory for verapamil plasma concentration measurements after oral administration because of the appearance of fluorescent metabolites (MCAllister et aI., 1979). A method which combines gas-chromatography (GC) with mass spectrometry (MS) seems to be the most sensitive and specific analytical tool available (Spiegelhalder and Eichelbaum, 1977). This technique has been used to study the disposition kinetics of 14C-D,L-verapamil following intravenous and oral administration to healthy volunteers (Schomerus et aI., 1976). Recently, this method was used to evaluate the pharmacokinetics of verapamil using stable isotope-labelled and unlabelled parent drug after oral and intravenous administration in 6 healthy young normal subjects (Eichelbaum et aI., 1981). The use of thermionic specific detectors which are sensitive to nitrogen (Hege, 1979; Nelson et aI., 1979; Todd et aI., 1980; Vasiliades et aI., 1982) has improved the usefulness of gas-liquid chromatography (GLC) techniques which originally lacked sensitivity (McAllister et aI., 1979). GC methods generally do not detect more than 1 major metabolite of verapamil (norverapamil), require a relatively large amount of plasma (1 to 2 ml), and in most cases involve time consuming and complicated extraction procedures. High-pressure liquid chromatography (HPLC) with fluorometric detection has been used effectively to separate and quantitate verapamil as well as its major metabolites (Cole et aI., 1981; Harapat and Kates, 1980; Jaouni et aI., 1980; Todd et aI., 1980). HPLC is the method of choice for verapamil pharmacokinetic studies in laboratories which do not have a mass spectrometer routinely available, since it offers sensitivity equal to that found with GLC methods (Todd et aI., 1980) and has the advantages of speed, smaller sample size requirement (0.1 to 1.0ml), simpler sample preparation procedures, and complete resolution of the major metabolites of verapamil (Cole et aI., 1981; Lim et aI., 1983). Future development of analytical techniques for
Clinical Pharmacokinetics of Verapamil
28
separation and quantitation of the individual optical isomers of verapamil would likely enhance the understanding of both the pharmacokinetic and pharmacodynamic properties of this drug.
2. Fundamental Pharmacokinetic Properties of Verapamil 2.1 Absorption Verapamil is rapidly and completely absorbed following oral administration (Schomerus et aI., 1976). The time to peak plasma verapamil concentrations averaged 2.2 hours in 20 normal subjects after doses of 80 and 160mg orally (McAllister and Kirsten, 1982). However, orally administered verapamil is subject to extensive first-pass hepatic elimination (extraction fraction = 0.79) from the portal circulation, resulting in a low systemic availability (10 to 20%) [Eichelbaum et aI., 1979; McAllister and Kirsten, 1982; Woodcock et aI.,
H3 CO
CN
H
1981 b]. Studies regarding the influence of food on the absorption of verapamil are not currently available. Relative bioavailability of a sustained release verapamil formulation compared with the conventional verapamil dosage form was almost 98% in patients with atrial flutter studied by Follath et aI. (1983); plasma concentrations Q.f verapamil were stable during 12-hour dosing intervals with the sustained release preparation. 2.2 Metabolism Verapamil is a papaverine derivative which is extensively metabolised by the liver in animals (McIlheny, 1971) and in man (Eichelbaum et aI., 1979) [see fig. 1]. Wide interpatient variation in drug metabolism is observed with verapamil, a finding consistent with drugs undergoing extensive first-pass extraction (Woodcock et aI., 1980). The
OCHs
H3CO-o-~-(CH~)s- ~-CH2- CH 2 0 0 C H
3
/c~ HsC
t
CHs
N-Demethylation
I
[6%]
O-Demethylation
N-Dealkylation
Fig. 1. Major metabolic pathways of verapamil in man. Percentages shown refer to the percentage of the total dose excreted In the urine within 48 hours (after Eichelbaum et al.. 1979).
29
Clinical Pharmacokinetics of Verapamil
majority of a radio-labelled dose of verapamil is excreted in the urine (70%) and faeces (15%) as inactive polar metabolites, with less than 5% of the parent compound being eliminated unchanged (Eichelbaum et aI., 1979). Primary metabolic pathways of verapamil include N-dealkylation and 0de methylation (Eichelbaum et aI., 1979). Although the products of O-demethylation possess pharmacological activity similar to verapamil (Neugebauer, 1978), these metabolites are excreted exclusively as inactive conjugates; therefore, their contribution to the overall pharmacological effect is insignificant. Norverapamil is an N-demethylated metabolite, which has been found after oral verapamil administration and which appears to have approximately 20% of the coronary vasodilator activity of the parent compound in dogs (Neugebauer, 1978). No data are available relating to the effects of norverapamil on the observed pharmacological responses to verapamil in man. Conventional drug assay techniques do not detect measurable quantities of metabolites of verapamil after single intravenous doses (McAllister, 1982).
accounted for approximately 70% of the binding variability found in a group of subjects with supraventricular tachyarrhythmia, even though it is by no means the major binding protein for verapamil (McGowan et aI., 1983). In vitro binding studies have shown significant decreases in verapamil binding in the presence of therapeutic concentrations of several weakly basic drugs (propranolol, diazepam, lignocaine, and disopyramide), and to a lesser extent with an acidic compound, salicylate (Yong et aI., 1980). Norverapamil, as well, has been shown to displace verapamil from its protein binding sites in vitro (Yong et aI., 1980). However, these interactions have not been confirmed in vivo. Verapamil binding is not decreased in patients with renal failure (Keefe et aI., 1981); information regarding the effect of other disease states on the protein binding of verapamil is not currently available.
2.3 Distribution and Protein Binding
In normal subjects, verapamil is widely distributed throughout body tissues. Experimental data in animals indicate that, after intraperitoneal administration to rats and intravenous administration to dogs, verapamil is found in relatively high concentrations in liver, kidney, lung, and heart tissues (Hamann et aI., 1983; Keefe et aI., 1982). The apparent volume of distribution (Vd area ) after intravenous drug administration in normal human subjects ranges from 162 to 380L (Dominic et aI., 1981; Eichelbaum et aI., 1981; Koike et aI., 1979; McAllister and Kirsten, 1982; Schomerus et aI., 1976). Verapamil is highly bound (90%) to plasma proteins in man, and the binding is independent of concentration over a range of 50 to 1500 ng/ml (Keefe et aI., 1981; Schomerus et aI., 1976; Yong et aI., 1980). In vitro studies have shown that verapamil is bound to albumin (60%) and to ai-acid glycoprotein (McGowan et aI., 1983). In vivo studies, in addition, revealed that ai-acid glycoprotein
1 2 3 4 6 Time after infusion (h)
8
10
Fig. 2. Plasma concentrations of verapamil as a function of time following intravenous administration of a 1Omg dose to a normal male subject (from McAllister and Kirsten, 1982: with permis· sion).
Clinical Pharmacokinetics of Verapamil
30
Eichelbaum et a1., 1981; Koike et a1., 1979; McAllister and Kirsten, 1982; Shomerus et a1., 1976). Wide variation in subject size, experimental design, analytical assay methodologies, and data analysis techniques have contributed to the problem of interpretation of the kinetic data available for verapami1.
90 80 70
E
60
Cl 50
.s c:
0 .~
3. Disposition Kinetics
40
E
"'c:0" " 'E
.. .
30
c.
Q; > 20
E
'" ~
10
11
•
.~
I
•
i
I
..............
I
I
I
1
I
I
I
I
I
I
., I
1 2 3 4 5 6 7 8 9101112 Time after dose (h)
Fig. 3. Plasma verapamil concentrations following an 80mg oral dose to the same subject as shown in figure 2 (from McAllister and Kirsten, 1982; with permission).
2.4 Elimination After intravenous (fig. 2) and oral (fig. 3) administration, verapamil plasma concentrations have been shown to decline in a mono-, bi-, or triexponential manner both in animals (Keefe and Kates, 1982; McAllister et a1., 1977) and man (see table I). Norverapamil is rapidly generated after oral administration, as represented in figure 4. Metabolic clearance of verapamil is the predominant pathway of elimination, constituting greater than 98% of the total plasma systemic clearance (Anderson et a1., 1982). Consequently, there exists wide intersubject variation in both the intrinsic and systemic clearances of verapamil, resulting in up to a 16-fold variation in systemic clearance values reported for normal subjects (Dominic et a1., 1981;
Data from studies which have analysed the pharmacokinetics of verapamil and norverapamil after single intravenous (fig. 2) and single oral (figs 2 and 3) administration to normal subjects are summarised in table I. In a recent study involving the largest number of subjects (McAllister and Kirsten, 1982), the reported apparent terminal elimination phase half-life for verapamil ranged from 2.7 to 4.8 hours. The mean systemic clearance of verapamil was 875 ml/min and, as would be expected with a compound subject to high first-pass elimination, the mean apparent oral clearance values were much greater, ranging from 4306 to 4830 ml/min. The mean apparent volume of distribution (Vd area) ranged from 310 to 406L. The results of studies employing a spectrophotofluorometric assay for verapamil quantitation (Koike et aI., 1979) should be viewed with caution, since fluorescent metabolites are generated after oral drug administration (McAllister et a1., 1979). The disposition of norverapamil has been examined following single oral doses of verapamil in normal subjects (McAllister and Kirsten, 1982), and after multiple oral doses in patients with angina pectoris (Frishman et a1., 1982; Tartaglione et a1., 1983). Plasma concentrations of the metabolite were linearly related to those of the parent compound, both after single doses (r = 0.88) and during sustained therapy (r = 0.86), using data presented in the studies cited above. The ratio ofverapamil AVC to norverapamil AUC has been consistently reported to be less than 1.0, which suggests that the pathway responsible for N-demethylation of verapamil is unsaturated over clinical dosing ranges (Freedman et a1., 1981; Shand et a1., 1981; Tartaglione et aI., 1983).
8
6 6
20 20 20 20
Oominic et al. (19Bl)
Eichelbaum et aJ. (1981)
McAllister and Kirsten (1982)
CLo
HPlC HPlC HPlC HPlC
MF MF
GlC
GlC GlC
HPlC HPlC
SPF SPF
MF MF
297.3±61.9
3.69d 3.S1d 4.B±2.4 4.S±2.4 3.7±1.8 4.8±3.8
34.3±15.4 3B4.9±83.0
296±67
IS8.4±26.9
62.7±24.9c
154±9.0
310.8±217.1c
Vd ••
ISI.1 ±34.9 87.9±65.0
1.84
2.8±1.2
2.0±0.5 2.7±0.S
4.S±I.9 4.2±I.S
S.3±2.3 3.1 ±O.39
Vc
Volume of distribution (L)
347.3± 184.8c 406.S±310.4c 310.4 ± 162.6c 399.1 ±32S.2c
41B.H 109.1
178±26
112.S±33.0
173.0±31.1 256.9± 12S.3c
380±72.7 360.3±19.0
Vdarea
= oral; MF = mass fragmentography; GLC = gas-liquid chromatography; HPLC
IV PO PO PO
IV PO
1080-
10801200 120-
IV
IV PO
IV PO
IV PO
IV PO
0.2 mglkg-
SBOO
6.5 120-
101200
10-
(h)
so-
Route Assay t,h.6
Dose
(mg)
= apparent oral clearance; CLs = apparent systemic clearance; F = bioavailability.
Plasma or serum clearance.
(47-84) 6S.8±16.4
(47-94) (39-64)
Calculated from original data. Harmonic mean. Abbreviations: IV = intravenous; PO
c d
Single doses.
a
b
2S±3.6 25±3.6 25±3.6 2S±3.6
(21-27) (21-27)
(24-28)
(29-64) (73-87)
4 2
Woodcock et al. (1981a)
64.7±S.7 64.7 ± 5.7
(21-31) (21-31)
6 6
69±16.7 79±16.5
(kg)
weight
Johnston et aJ. (1981)
6S±S "56±7
age (y)
37.S± lB.4 64.7±10.1 37.S±18.4 64.7±10.1
3 3
ber
num-
Subjects
Koike et a/. (1979) 6 6
Schomerus et al. (1976)
Reference
Table I. Verapamil pharmacokinetic parameters in normal subjects (all data given as mean ± SO, or ranges)
874.5 ± 369.5
12S7.7±193.1
1060±270
1571 ±405
1039.4 ± 402.1 c
SOO.6±177.1
868.2±218.6
CLsb
F
18±10.1 19.8±IS.4 20.4±12.1
22±7.9
19.3
2.2±9.2
22.S±3.3
10.5
(%)
high-pressure liquid chromatography;
4830.9 ± 2030.4 4492.4 ± 2821.4 4306.6 ± 2058.7
6383.3±2319.6
5439.7 ± 27S8.9c
2752.4 ± 869.3
622.1 ±41B.lc
Clob
Clearance (ml/min)
0
...,
~ ~
<:
a ..,0
g.
er. ::I
~
,.,0
§
::r ~
'"t!
S·
o· e:.
32
Clinical Pharmacokinetics of Verapamil
3.1 Non-Linear Kinetics Non-linear pharmacokinetics with verapamil have recently become an important consideration and remain somewhat controversial. The drug has a relatively high systemic clearance with a low oral bioavailability secondary to extensive presystemic elimination. Kates et aI. (1981) utilised model-independent parameters generated from single-dose intravenous data to effectively predict steady-state plasma concentrations following a multiple-infusion scheme designed to achieve plasma drug concentrations over a range of 19.6 to 118.5 ng/mI. This study suggested linear pharmacokinetics following intravenous therapy. In contrast, Bourne et al. (+ unpublished data, 1980) found that a pharmacokinetic model derived from single intravenous doses in normal subjects, constructed to allow rapid achievement of predicted plasma verapamil concentrations and maintenance during continuous infusion, was accurate for drug levels below 60 ng/ml but progressively underestimated drug concentrations above this figure. A linear relationship was observed between dose and area under the plasma concentration-time curve (AUC) following the single oral administration of 80, 120 and 160mg of verapamil to normal subjects (McAllister et aI., 1982). Non-linear accumulation of verapamil has been observed, however, following multiple oral doses (Freedman et aI., 1981; Kates et aI., 1981; Shand et aI., 1981; Wagner et aI., 1982), suggesting either an increased systemic bioavailability or decreased systemic clearance. The plasma concentration ratio of verapamiljnorverapamil remained unchanged over a daily dose range of 240 to 480mg, which indicates that metabolic conversion of verapamil to norverapamil is not· concentrationdependent (Frishman et aI., 1982). Despite verapamil's non-linear characteristics following multiple-dose oral administration, Wagner et al. (1982) [through the re-evaluation of data from Freedman et aI., 1981 and Shand et aI., 1981] demonstrated that steady-state concentrations were, in fact, predictable; their calculations revealed only a modest variation in the percentage reduction in oral clearance from person to person (a 2.4-fold
decrease in clearance was generally observed) with multiple-dose administration. In summary therefore, the systemic clearance of verapamil appears to be independent of concentration following administration of single intravenous doses; controversy exists regarding the linearity of verapamil phalmacokinetics during sustained intravenous infusions. Oral clearance and systemic bioavailability following single oral administration appear to be independent of dose. Remarkable but predictable decreases in oral clearance following multiple-dose oral therapy have been observed. The mechanisms involved in the observed non-linear accumulation following multiple oral doses of verapamil are not understood at the present time.
4. Pharmacokinetics in Disease States 4.1 Liver Disease Since verapamil is eliminated by the liver and undergoes significant first-pass metabolism, one would anticipate that altered hepatic function might result in changes in the drug's intrinsic and systemic clearances, as well as systemic bioavailability. The pharmacokinetics of verapamil after a single intravenous dose were compared in normal subjects and in 5 patients with biopsy-confirmed liver disease (Woodcock et aI., 1981a) [see table II] characterised as follows: 2 had hepatic cirrhosis associated with alcohol abuse; 1 had cardiac cirrhosis; 1 had cirrhosis of uncertain aetiology; and 1 patient had acute fatty changes due to alcohol toxicity. Following a 5mg intravenous dose, the subjects with liver. dysfunction showed a 3-fold decrease in systemic clearance and a 1.7-fold decrease in apparent volume of distribution (Vd area), with a corresponding increase in the plasma half-life. Somogyi et al. (1981) evaluated more completely the disposition and bioavailability of verapamil, studying 7 patients with histologically proven hepatic cirrhosis (postinfectious or alcoholic). All subjects received intravenous unlabelled and oral trideuterated verapamil simultaneously, to assess both oral and systemic clearance. As can be seen from table II, all of the pharmacokinetic parameters evaluated were altered. The volume of
2;4 5; 4 12; 4
CAF CAF
CAS;NL CAS; NL CAS;NL
HCM
AF AF
SVT AP
Kates al al. (1981)
Freedman
Wagner el al. (1982)
Anderson et al. (1982)
Reiter et al. (1982)
9 6
6 6
7
6 6
age
45±lS.0 62 ± 4.2
58±3.7 58±3.7
12±4.4
47±9.3 48±8.5 50±8.4
60±4.0 60±4.0
(36-37) (36-37)
49±16.3 (21-27)
70.3±14.5 83.9 ± 11.3
76±16.2 76± 16.2
55±24.5
79±13.5 77±14.1 73±1S.7
81 ±19.5 81 ±19.5
65.1 ±12.2 (47-85)
70.2±13.9 74.8±20.0
62
44
44±9.0 38±7.0
62
weight (kg)
44
(y)
10" 80-160b
10· 80·
0.1 mg/kga
10-15· 80· 80'
15120-
120120b
10; 4010; 40-
5· 5·
10; 40·
10; 40·
Dose (mg)
GLC GLC
IV PO
IV PO
IV
IV PO PO
IV PO
PO PO
9.2±6.0
5.00 5.7" 9.8"
6.3±4.0 8.2±6.1
2.8± 1.1 4.5±1.1
14.2 3.7
13.6±3.9 2.9±1.2
15.3
15.7
(h)
t1h~
HPLC HPLC
2.1±1.2S
GLC-MS S.8±1.77 GLC-MS S.S±1.49
GLC
HPLC HPLC HPLC
HPLC HPLC
HPLC HPLC
IV; PO MF IV; PO MF
IV IV
IV; PO MF
IV; PO MF
Route Assay
10:8
17.00
33.S±
29.2 ±27.2
28.6 ±24.0
141.9 314.2
120.3
114.1
Vc
390±76
457.1 ± 168.5d
784.5 446.2
528± 142 380±127
542.5
530.7
Vd.,••
103±8S.7d 161 ±111.7
279±244.3 394±362
267±52
323.9 ±109.6
597.0 403.9
461.3
445.2
Vd ••
Volume of distribution (l)
1906±972
3757.8±1666.5
4160.9± 1959.3d 1644.5 ± 734.6d
2720 ± 780d 1040±210d
1300.0 6300.0
477.6 d
1024.1"
CLoc
793.3
312.6 ± 169.2
499.7 ± 248.4
860±112
1052.1 ±568d
616.4 1258.0
529± 176 1619±415
363.9
391.2
Clsc
Clearance (ml{minJ
24±10
35±16
52.3 22.0
81.5
38.2
F ("/oj
=
a Single dose; b Given a-hourly till steady-state at seventh dose; c Plasma or serum clearance; a Calculated from original data; e Harmonic mean; f given 6-hourly till steady-state. Abbreviations: lD = liver disease; MeBS = meso-caval bypass surgery; Nl = normals; SVT = supraventricular tachyarrythmias; CAF = chronic atrial fibrillation; CAS coronary artery spasm; HCM = hypertropic cardiomyopathy; AF = artrial fibrillation; IV = intravenous; PO = oral; MF = mass fragmentography; GlC = gas-liquid chromatography; HPlC = high-pressure liquid chromatography; MS = mass spectrometry; CLo = apparent oral clearance; Cl. = apparent systemic clearance; F = bioavailability; AP = angina pectoriS.
et al. (1981)
12 12
SVT SVT
Shand et al. (1981)
7 6
LD NL
Somogyi et al. (1981)
5 4
LD NL
Woodcock et al. (1981a)
number
LD MCBS (before) MCBS (after)
status
Patients
Eichelbaum et al. (1980a)
Reference
Table II. Verapamil pharmacokinetic parameters in disease states (data given as mean ± SO, or ranges)
3
...., ....,
g,
'0 Il>
@
<:
'"0...,
(")
::>
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er.
0
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I»
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0
S·
Clinical Pharmacokinetics of Verapamil
the central compartment (Ve) was reduced by 54%; Vd ss and Vdarea were increased by 44% and 78%, respectively, and oral and systemic clearance were reduced 5- and 2-fold. An increase in the terminal plasma half-life from 3.7 to 14.2 hours was also observed. Increases in the distribution volume could not be explained by changes in plasma protein binding, and these investigators suggested that increased tissue binding might be present. Following oral administration, subjects with liver disease showed higher peak drug concentrations, shorter times to achieve maximum drug plasma concentrations, and a significant increase in systemic bioavailability (22.0% vs 52.3%). Verapamil systemic clearance was strongly correlated with antipyrine clearance (r2 = 0.73, p < 0.01) but, surprisingly, not with indocyanine green clearance (r2 = 0.01). From available data, it would seem appropriate that in patients with liver disease, single intravenous doses of verapamil should be decreased by half, and the oral dose decreased by a factor of 5. The influence of mesocaval shunt surgery was evaluated in a 62-year-old patient with hepatic failure (Eichelbaum et aI., 1980a), using simultaneous administration of intravenous (unlabelled) and oral trideuterated verapami!. The only parameter significantly altered by surgery was systemic bioavailability. Changes in hepatic blood flow (indocyanine green clearance 447.6 mljmin before vs 165.2 mljmin after) appeared to have little effect on the systemic clearance of verapamil (391.2 mljmin before vs 383.9 mljmin after). This observation supports the conclusion of Somogyi et al. (1981) that verapamil systemic clearance may be more dependent on the microsomal hepatic enzyme systems than on changes in liver blood flow. 4.2 Cardiovascular Disease Verapamil is a drug which is principally prescribed for patients with various cardiovascular disorders. Although it has been shown that cardiac disease can alter the pharmacokinetic characteristics of other drugs which undergo extensive firstpass metabolism and have systemic clearances approaching hepatic blood flow, well-controlled stud-
34
ies of the effects of various cardiac disorders on the disposition of verapamil are unavailable. 4.3 Renal Disease Available data from recent work demonstrate that the pharmacological responses to and the disposition of verapamil are similar in normal subjects and in patients with chronic renal failure (Shols et aI., 1983).
5. Plasma Concentration-Effect Correlations Concentration-dependent electro physiological etTects of verapamil have been studied in vitro using isolated cardiac muscle preparations both from animals (Imanishi et aI., 1978; Rosen et aI., 1974) and man (Hordof et aI., 1976). In 1 investigation, the apparent depressant effects on both rate and overshoot of slow channel-dependent spontaneous depolarisations were related directly to verapamil concentrations in the depolarised guinea-pig ventricular myocardium (Imanishi et aI., 1978). In vivo studies, using both conscious and anaesthetised open-chest dogs, supported earlier in vitro findings regarding the range of concentrations associated with verapamil-induced effects. A 10glinear relationship has been found between plasma verapamil concentration and the delay in atrioventricular conduction time in conscious dogs (McAllister et aI., 1977) as well as in open-chest anaesthetised dogs (Mangiardi et aI., 1978). This log-linear relationship exists for both plasma and myocardial tissue verapamil concentrations (Keefe and Kates, 1982). There is a close correlation between the electrophysiological effects and the logarithm of plasma drug concentration following initial intravenous doses in man (Eichelbaum et aI., 1980b; Koike et al.. 1979; McAllister and Kirsten, 1982; Sakurai et al.. 1983; Sung et aI., 1980) [see fig. 4], although considerable intra- and intersubject variation in response to specific plasma drug concentrations does exist. After intravenous, but not oral, verapamil administration, there is a 15 to 30 minute lag time
Clinical Pharmacokinetics of Verapamil
before decreases in A-V conduction time and plasma drug concentrations correlate linearly (Eichelbaum et aI., I980b; McAllister and Kirsten, 1982). Endogenous sympathetic tone and the underlying functional state of the cardiovascular system have been found to be major determinants of individual responses to verapamil. The importance of sympathetic tone in determining the electrophysiological response to verapamil was demonstrated in animal studies showing that after propranolol or reserpine pretreatment, previously well-tolerated plasma concentrations of verapamil resulted in high degrees of atrioventricular block (Urthaler and James, 1979). Furthermore, ventricular rate responses in patients with atrial flutter and fibrillation are reduced at lower plasma verapamil concentrations in the absence of cardiac failure and associated increases in sympathetic tone (Dominic et aI., 1979). Clear differences in the
80 70 60 50
E
40
0;
.s c:
'"~ 0
.
30
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f\
( \.
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c:
8
E
20
'"
c.
~ ~ 0
c:
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(/)
a::'"
10
1 2 3 4 5 6 7 Time after dose (h)
8
9 10 11 12
Fig. 4. Plasma concentrations of the metabolite. norverapamil. after an 80mg oral dose of verapamil to the same subiect as in figures 2 and 3 (from McAllister and Kirsten. 1982; with permission).
35
haemodynamic responses to verapamil have been reported in patients with coronary artery disease and depressed left ventricular ejection fraction when compared with patients with similar anatomical coronary disease but only mild to moderate decreases in ejection fraction (Chew et ai., 1981). Conventional doses of verapamil may result in atrial arrest and/or asystole in patients with sinus node dysfunction (Carrasco et aI., 1978; Mertens et aI., 1980). Few studies have been concerned with plasma verapamil concentration/pharmacological effect correlations after oral drug administration. A therapeutic range of verapamil plasma concentrations between 100 and 400 ng/ml has been reported in 31 patients with hypertrophic obstructive cardiomyopathy, although a 3D-fold variation in trough plasma concentrations was found with the fixed dose regimen used (Woodcock et aI., 1980). In a similar patient population, Leon et ai. (1981) found it difficult to differentiate between patients with good clinical response to the drug, non-responding individuals, and those with serious drugrelated side effects by analysis of plasma verapamil concentrations. A range of plasma verapamil concentrations from 150 to 500 ng/ml has been associated with increasing exercise capacity in patients with stable angina pectoris given oral verapamil (Anderson et ai., 1982), although a similar study reported that plasma drug concentrations over the same range could not reliably predict the clinical response of individual patients with angina (Frishman et aI., 1982). However, plasma concentrations > 100 ng/ml were associated with improvement, and peak verapamil concentrations up to 900 ng/ ml were found in this patient population, without adverse effects. Further, norverapamil has not been shown to contribute to the antianginal activity of the parent compound. The plasma verapamil concentrations required for a given increase in A-V conduction time after single oral doses appear to be 2 to 3 times greater than those after intravenous administration to the same normal subjects (see fig. 5). This difference has been attributed to presystemic stereoselective elimination of the more active L-isomer of vera-
Clinical Pharmacokinetics of Verapamil
36
pamil (Eichelbaum et aI., 1980b), although recent animal studies have indicated that verapamil is concentrated to a greater extent in myocardial tissue after intravenous administration than after simulated oral administration (Hamann et aI., 1983). To further complicate the determination of the pharmacodynamic properties of verapamil after oral administration, it has been reported that the effect of verapamil on P-R interval prolongation decreases or disappears during multiple-dose oral therapy (Reddy et aI., 1981). The role of verapamil as an antihypertensive agent has been reviewed by Spivack et al. (1983). Controversy exists at this time, however, regarding possible correlations between the drug's hypotensive effects and corrcsponding plasma drug concentrations (Semplicini et aI., 1982; Storstein et aI., 1981). At the present time, it appears that the complexity of pharmacodynamic evaluation of verapamil after intraven-
ous or oral drug administration has made measurement of plasma drug concentrations useful largely in evaluation of non-responding patients, since a 'therapeutic' range of plasma drug concentrations has not yet been defined. Although delineation of a toxic plasma concentration of verapamil after oral drug administration is not possible from available data, cardiovascular toxicity(includingsymptomatichypotension, bradycardia and atrioventricular block, and even asystole) has been reported after intravenous verapamil and with massive oral doses (Candell et aI., 1979; deFaire and Lundman, 1977).
6. Drug Interactions 6.1 Digoxin The combination of verapamil and digoxin has been shown to be useful in decreasing ventricular response rate in patients with chronic atrial fibril-
50 U
en
S
40
(ij
>
Oi
~
30
"2
20
a: ci.
C 0
u
E
g
10
Cl
C
ro
.c u
0
c ro
~
-10
10
20
3D
40
50
60
70
80 90 100
Mean plasma verapamil concentration (ng/ml)
Fig. 5. Correlation of plasma verapamil concentrations with corresponding effects on P-R interval duration following single intravenous or oral verapamil doses in 20 normal subjects (from McAllister and Kirsten, 1982; with permission).
Clinical Pharmacokinetics of Verapamil
Jation, especially during exercise. Increases in sensitivity to digoxin, with occasional induction of higher degrees of atrioventricular block, may result when verapamil is added to the glycoside. Recent clinical studies have documented significant increases in plasma digoxin concentrations during verapamil treatment (Klein et a!., 1980; Schwartz et a!., 1982), with the suspected development of digitalis toxicity in 14% of patients given the 2 drugs together (Klein et a!., 1980). More rigorous pharmacokinetic analysis of this drug interaction has revealed that verapamil significantly decreased the apparent central distribution volume and prolonged the biological half-life of digoxin (Klein et a!., 1982; Pedersen et aI., 1981). Furthermore, verapamil reduced the total body clearance of digoxin by 39%, decreasing both renal (20% reduction) and extrarenal (60% reduction) drug clearance (Pedersen et aI., 1981). The renal interaction between digoxin and verapamil has shown no concentration or dose dependence over a dose range of 240 to 360 mg/day (Belz et aI., 1983). Changes in the renal component of digoxin clearance may be attributable to altered renal tubular secretion, since glomerular filtration rates are not affected (Belz et aI., 1983; Pedersen et aI., 1981, 1983). 6.2 8-Adrenoceptor Blocking Drugs Combination therapy with propranolol and verapamil has been shown to be more effective in the treatment of angina pectoris than either drug used individually, but largely in fixed dose studies (Ba\a Subramanian et aI., 1982; Bowles et aI., \981; Leon et aI., 1981). However, there have been reports of severe cardiovascular depression resulting from coadministration of verapamil and 8-adrenoceptor blocking agents (Benaim, 1972; Denis et aI., 1977; Krikler and Spurrel, 1974; Nayler et aI., 1968; Seabra-Gomes et aI., 1976). The mechanism of this potentially dangerous interaction has not been elucidated, although both clinical studies (Bala Subramanian et aI., 1982; Leon et a!., 1981; Packer et a!., 1982) and a report which evaluated the effects of intravenous doses of propranolol given to dogs receiving constant intravenous infusions of vera-
37
pamil (Hamann et aI., 1982) suggest the dependence of this interaction on the relative plasma concentrations of both verapamil and propranolol. Clearly, close monitoring of al1 patients receiving these drugs together is essential.
7. Therapeutic Drug Monitoring Considerations Verapamil would appear to have the necessary characteristics to make routine therapeutic drug monitoring procedures worthwhile: (I) it has both broad therapeutic and toxic potential, since it interferes with basic biological processes involving availability of calcium ion; (2) both animal and patient studies, with single intravenous doses of the drug, have shown good correlations between plasma concentrations of the drug and prolongation of the P-R interval; and (3) very wide variations in drug disposition exists between individuals. However, the intra- and intersubject variability in intensity of drug effects seen at specific plasma drug concentrations, particularly after oral administration, has made definition of a 'therapeutic' range difficult. This problem may relate, at least in part, to the fact that endogenous catecholamines may antagonise the pharmacological effects of verapamil, and that sympathetic tone varies considerably from one individual to another. Furthermore, as noted in preceding sections, the pharmacodynamic characteristics of verapamil are clearly influenced by underlying haemodynamic and electrophysiological status. In view of these considerations, it is difficult to argue a persuasive case for routine monitoring ofverapamil plasma levels. We feel that such measurements are of particular use in determining patient compliance or in estimating the bioavailability of drug in patients who appear to require very large doses ofverapamil for minimal apparent drug effect.
8. Dosing Considerations Single intravenous doses ofverapamil, generally given for control of ventricular rate in patients with supraventricular tachyarrhythmias, com-
Clinical Pharmacokinetics of Verapamil
monly range from 0.075 to 0.2 mg/kg (Dominic et aI., 1979; Singh et aI., 1980; Sung et aI., 1980). Although a reasonable approach, the use of verapamil by bolus and sustained intravenous infusion has not been widely used. Chew et al. (1981) gave a usual bolus with an infusion of 0.005 mg/kg/min over an hour, maintaining plasma drug concentrations of about 100 ng/m1. Reiter et a1. (1982) reported a different approach, using a loading bolus dose followed immediately by a 'loading infusion' and then a maintenance infusion, to produce and maintain stable plasma verapamil concentrations between 77 and 156 ng/m1. In our experience (unpublished) in 6 normal subjects, a loading dose of 8.5mg (over 3 minutes) followed by an infusion rate of 0.25 mg/min (0.0035 mg/kg/min) produced mean plasma verapamil levels of 165 to 204 ng/ ml over a 3-hour study period. Obviously, the presence of altered hepatic blood flow or function would make such regimens invalid. Oral verapamil administration results in wide variability in plasma concentrations among subjects (McAllister and Kirsten, 1982; Woodcock et aI., 1980). Since the kinetics of verapamil change with multiple-dose oral administration (Shand et aI., 1981), the situation becomes even more complex. Treatment with oral verapamil is usually begun at low dosage levels (80mg everyS hours), and increased at intervals until evidence of clinical efficacy or drug toxicity occurs. Although many studies have used 480mg daily as a peak dose, we have seen patients who require 800mg each day to sustain therapeutic effects. After a week of drug administration, dosing may be changed from thrice to twice daily, due to the prolongation of elimination half-time.
Acknowledgement The authors are grateful for the expert assistance of Mrs Bonnie Edens in the preparation of this manuscript.
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38
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Clinical Pharmacokinetics of Verapamil
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39
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Clinical Pharmacokinetics of Verapamil
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40
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41
Clinical Pharmacokinetics of Verapamil
Sung, RJ.: Elser, B, and McAllister, R,G,: Intravenous verapamil for tcrmination of re-entrant supraventricular tachycardias: Imracardiac studies correlated with plasma verapamil concentrations, Annals of Internal Medicine 93: 682-689 (1980), Tartaglione, T,A,: Pieper. JA: Lopez, LL and Mehta, J,: Pharmacokinetics of verapamil and norverapamil during long-term oral therapy, Research Communications in Chemical Pathology and Pharmacology 40: 15-27 (1983), Todd, G.D,: Bourne, D,W,A, and McAllister, R,G,: Measurement of verapamil concentrations in plasma by gas chromatography and high pressure liquid chromatography, Therapeutic Drug Monitoring 2: 411-416 (1980), Urthaler, F. and James, T,N,: Experimental studies in the pathogenesis of asystole after verapamil in the dog, American Journal of CardiOlogy 44: 651-656 (1979), Vasiliades, J,: Wilkerson, K,: Ellul, D,; Anticoli, M, and Rocchini, p,: Gas-chromatographic determination of verapamil and norverapamil, with a nitrogen-selective detector. Clinical Chemistry 28: 638-641 (1982), Wagner, J,G,; Rocchini, A,P, and Vasiliades, J,: Prediction of steady-state verapamil plasma concentrations in children and adults, Clinical Pharmacology and Therapeutics 32: 172-181 (1982), Woodcock, B.G,; Hopf, R, and Kaltenbach, M,: Verapamil and
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Author's address: Dr KG. McAllister Jr, Associate Chief of Staffj R&D (151), Veterans Administration Medical Center, Lexington, Kentucky 40511 (USA),
International Symposium on
Drug Responses in Relation to their Plasma Levels Date: May 18 & 19, 1984 Venue: Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart For further information contact: Dr J,C. Frolich, Professor and Head, Fischer-Bosch Institute of Clinical Pharmacology, Auerbachstrasse 112, 7000 Stuttgart 50, West Germany.