EUROPEAN JOURNAL OF DRUG METABOLISM AND PHARMACOKINETICS, 1991, Vol. 16, No.2, pp. 153-159
Absolute bioavailability of moxonidine 2
1
R. THEODORt, H.-I. WEIMANN , W. WEBER and K. MICHAELIS 1 1 LAB. GmbH & Co, Neu-Ulm, Germany 2 Kali-Chemie Pharma GmbH, Hannover, Germany
Receivedfor publication: October 1, 1990 Keywords: Moxonidine, human pharmacokinetics, absolute bioavailability, healthy volunteers
SUMMARY In a randomized 2-way cross-over study with eighteen healthy male volunteers, two moxonidine preparations (tablets, treatment A vs. intravenous solution, treatment B) were tested to investigate absolute bioavailability and pharmacokinetics of moxonidine. The preparations were administered as single doses of 0.2 mg; prior to and up to 24 h after administration blood samples were collected and the plasma moxonidine concentrations determined. Urine samples were collected prior to and at scheduled intervals up to 24 h after administration for the determination of unchanged moxonidine. Moxonidine plasma and urine concentrations were determined by a validated gas chromatographic/mass spectrometric method with negative ion chemical ionization. The mean areas under the plasma concentration/time curves were calculated as [mean ± standard deviation] 3438 ± 962 pg.h1ml (AUC(~T1Mt» and 3674 ± 1009 pg.h1ml (AUC(~oo» for treatment A; 3855 ± 1157 pg.h1ml (AUC(~Tlast» and 4198 ± 1205 pg.h1ml (AUC(O-t oo for treatment B. Mean peak plasma concentrations of 1495 ± 646 pglml were attained at 0.56 ± 0.28 h after oral treatment, mean peak plasma concentrations after intravenous treatment reached 3965 ± 1342 pglml at 0.17 ± 0.01 h (= coinciding with end of infusion). The mean terminal half-lives of moxonidine were derived as 1.98 h after administration of the tablet and as 2.18 h after infusion. The amounts of moxonidine excreted in urine during the 24 h following administration (Ae(24h» in absolute figures and as percentage of the dose administered were 102 ± 26 J.Lg or 51 ± 13% for the tablet and 122 ± 33 J.Lg or 61 ± 16% for the infusion.
»
The relative bioavailability of oral moxonidine (assuming the availability of the i.v. solution to be 100%) was calculated to be 89% or F = 0.89 (AUC(O-tTlast» and 88% or F = 0.88 (AUC(O-too». Taking these results into account, the relative amount of moxonidine excreted in urine of the dose absorbed comes up to approximately 58% for the tablet, which is comparable to an excretion of 61% of the dose administered (= absorbed) after i.v, administration. With the self-evident exception of CIIUlXt statistical testing of pharmacokinetic parameters revealed no significant differences between treatments.
INTRODUCTION Moxonidine, 2-methyl-4-chloro-5-(2-imidazoline-2ylamino)-6-methoxy-pyrimidine, is a new centrally acting antihypertensive agent It is a selective cz-adrenoceptor agonist that differs from other centrally acting a,2-stimulating antihypertensive agents in the following properties (1-3): Please send reprint requests to : Dr. H.-I. Weimann, Kali-Chemie Pharma GmbH, Hans-Beckler-Allee 20, D-3000 Hannover, Germany
• high a,z/a,I-selectivity ratio, • high selectivity for presynaptic cz-receptors. • full intrinsic activity at the cz-receptors. These characteristics have been suggested to be the main factors responsible for the reported lower incidence of side effects of moxonidine compared to the partial a,2-agonistclonidine-HCI (2). Following oral administration, 80-90% of the dose is absorbed from the gastrointestinal tract (4). After a single oral dose of 0.2 mg moxonidine, peak. plasma levels of 1.3 ± 0.3 ng/ml were reached after 0.7 ± 0.4 h. The drug is eliminated with a terminal half-life of
154
Eur. J. Drug Metab. Pharmacokinet., 1991, No.2
2.1 ± 0.6 h. No statistically significant alterations are reported after repeated dosing (5). About 7% of moxonidine is bound to human plasma proteins. About 10% of moxonidine is metabolized to 4,5-dehydromoxonidine and, by opening of the imidazoline ring, to a guanidine derivative. These metabolites show less than 10% and 1%, respectively, of the blood pressure reducing potency of the parent drug. The elimination of moxonidine and its metabolites is predominantly by the renal route. Over 90% of the applied radioactivity is eliminated in the first 24 h after administration, about 1% in feces (4). Multiple oral dosing in hypertensive patients resulted in a persistent blood pressure reduction, supine as well as standing (6). After treatment with a mean daily dose of 0.3 mg of moxonidine, blood pressure was strongly reduced during the first three weeks, after this decreasing only slightly. After one year treatment, mean supine systolic and diastolic blood pressure reduction was -24/-18 mmHg (7). Heart rate remained almost uninfluenced. Biochemical and hematological parameters (mean values) did not change significantly (7). The hypotensive effect of moxonidine is mainly caused by a decrease in peripheral resistance, while cardiac output remains unchanged (8). This finding corresponds to the observation, that moxonidine showed very good efficacy in patients older than 60 years of age (7). The most common adverse drug reactions are dryness of mouth and fatigue. Other observations had been, for example, headache, vertigo, nervousness, nausea, orthostatic dysregulations. Withdrawals due to adverse drug reactions were reported in about 2% of participants. Serious adverse drug reactions have not been observed. Contraindication for a treatment with moxonidine is a sick sinus syndrome. The recommended dose range is 0.2 to 0.6 mg/day, given once daily or b.i.d.. The highest dose of 2.0 mg/day moxonidine revealed no serious adverse drug reactions (ADR) (7).
e
The only data available on absolute bioavailability were derived from a study with 4C]-radiolabelled moxonidine, performed in 6 volunteers in 1986 (4). At that time, no sophisticated analytical methods for unchanged moxonidine, such as the GC/MS method used for the present study were available. The aim of this study was to detennine absolute bioavailability and pharmacokinetics of moxonidine in man following oral and intravenous administration of 0.2 mg to healthy male volunteers under single dose conditions using state-of-the-art technology.
MATERIALS AND METHODS Study design The study was performed as an open, randomized, single-dose, two-period crossover study. The study periods were separated by a wash-out phase of five days. After an overnight fasting period the participants received a single dose of 0.2 mg moxonidine via the oral or intravenous route in a randomized sequence order. The first meal was served 4 h after drug administration. During each study session the volunteers were confmed for two nights and one day (observation period approximately 36 h). When not confmed to the study site, the volunteers maintained their normal daily activity, but were instructed to report any event, which might have an influence on the study performance. All adverse events or adverse drug reactions occurring during the study were documented.
Subjects Nineteen healthy male volunteers between 20 and 48 years of age were enrolled in the study. Eighteen of them completed the study, one subject dropped out for personal reasons after period 1. The mean age ± standard deviation of the subjects completing the study was 31.7 ± 9.5 years, the mean body weight was 74.8 ± 5.6 kg, the mean height was 179.3 ± 7.4 em. A prestudy and poststudy examination was performed including physical examinations and extensive laboratory screenings. Written voluntary consent was obtained from all subjects. Prior to initiation, the study had been approved by an independent ethical committee. During a two week period preceding the study and for the entire duration of the study no drug treatment other than the test preparations were allowed. Furthermore, the consumption of caffeinated or alcoholic food or beverages as well as extensive physical activities were not allowed during periods of confinement to the study site.
Drug application Moxonidine was given as 0.2 mg tablets (batch 051 G, treatment A) or as an intravenous solution with a strength of 0.4 mg/2 ml (batch 059 G, treatment B). The dose was 1 tablet or 1 ml of the solution. The
R. Theodor et al., Absolute bioavailability of'moxonidine tablet was taken with 200 ml of water in an upright position. The infusion solution was prepared by diluting 2 ml (= 0.4 mg) of the moxonidine solution with physiological saline up to a volume of 20 ml. Ten ml of this solution (= 0.2 mg of moxonidine) were administered in a sup-ine position by means of an infusion pump (Perfusor®, Braun-Melsungen) at a constant infusion rate of 1 ml/min over a period of 10 min. For this purpose an indwelling catheter was used, which was placed on the ann contralateral to the one used for blood samplings.
Blood samples and urine collection Blood samples of 10 ml each were collected by an indwelling catheter or by individual venipuncture with a steel canula into lithium-heparinized Sarstedt Monovettes® (Sarstedt, Niirmbrecht, Germany) at the following times: • oral application: predose (before drug administration) and 10, 20, 30, 45, 60, 90 min and 2, 2.5, 3, 3.5,4,6, 8, 10, 12, 14, 16 and 24 h after drug administration; • intravenous application: predose (before drug administration) and 5,10, 15,20,30,45,60, 90 min and 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 14, 16 and 24 h after start of infusion. Directly after collection, blood samples were centrifuged for 15 min at +4°C at 3000 g and the resultant plasma supernatant stored at -20°C until analysis. Urine samples were collected prior to dosing and during the following intervals thereafter for both routes of administration: • predose (before drug administration) andfrom 0-3, 3-6, 6-9, 9-12 and 12-24 h afterwards. At the end of each interval the volunteers were required to empty their bladder. The volume and pH of each sample were measured and documented. An aliquot of 50 ml was taken and stored at -20°C until analysis.
Safety parameters Blood pressure and heart rate were monitored by a sphygmomanometric semiautomatic device (BOSO Digital IT S, Bosch + Sohn) at the following times, (after the blood sample had been withdrawn, if coinciding): • oral application: predose and 1,2,4,8 and 12 h;
155
• intravenous application: predose and 10,20, 40 min and 1, 1.5,2,4,8 and 12 h. A 12-lead-ECG was registered prior to the drug applications and during the poststudy examination. Adverse events and adverse drug reactions were evaluated by open questioning or by spontaneous reports of the volunteers. On the evening prior to the drug applications a short interview with a physician was performed,
Analytical approach For the quantitative determination of moxonidine in plasma and urine, a validated gas chromatographic} mass spectrometric method (GC/MS) with negative ion chemical ionization was used (9).
Calculation of pharmacokinetic parameters Phannacokinetic parameters were derived from the analytical data by means of the TOPFlT computer program (Dr Karl Thomae GmbH, Biberach/RiB, Germany) using an open two-compartment model with lag time. The oral data of subjects 15 and 16 were evaluated with an open one-eompartment model with lag time. The parameter Ae(24h) was assessed directly from the renal excretion data (see Table I).
Statistical analysis After logarithmic transformation, the parameters Cmax, AUC(~Tlast), AUC(~oo), tlfl 1..2 and Ae(24h) were analyzed according to the Grizzle model for cross-over trials without interaction between period and treatment The two one-sided t-tests procedure (10) for equivalence within the (80%, 125%) range and the two-sided t-test for treatment difference were applied. Conventional 90% and 95% confidence intervals were calculated.
RESULTS AND DISCUSSION A total of 19 volunteers was enrolled into this study. Eighteen of them completed the trial in accordance with the protocol. One subject dropped from the study due to personal reasons after completion of period 1.
Eur. J. Drug Metab. Pharmacokinet., 1991, No.2
156
Table I : Pharmacokinetic parameters derived from the analytical data Parameter
Unit
tin. a
h
Definition Absorption half-life (oral dosing only)
tIn. 1..1
h
Distribution half-life
tin. A.2
h
Termimal half-life
tmax
h
Peak plasma concentration of the fitted curve
C max
pglml
Time to peak plasma concentration of the fitted curve
AUC«HTIlm)
pg.hJml
AUC until last quantified sample using the trapezoidal rule with lag-time
AUC«Hoo)
pg.hJml
AUC of the fitted curve until infinity
Vd
lIkg
Volume of distribution in the central compartment
Vas
lIkg
Volume of distribution in steady state
CLtot
mlIminlkg
Total clearance
MIT
h
Mean transit time
Ae(24h)
J.Lg
Amount excreted
Ae(24h)
% of dose
Amount excreted
Therefore, 18 completed cases could be taken into the evaluation. After oral application, 7 subjects reported adverse drug reactions, mild in intensity; the symptoms had been headache and tiredness. After intravenous application, 3 subjects reported adverse drug reactions, mild in intensity; the symptoms had been headache, tiredness and dryness of mouth. None of the adverse drug reactions needed treatment, the drug relation was rated possible (= 2) in each case according to a five-step rating scale (Adverse Event Form, Kali Chemie). A relevant difference between the treatments could not be found regarding the quality of adverse drug reactions. The poststudy examination revealed no relevant changes during the physical and laboratory examinations as compared to the prestudy examination. Blood pressure and heart rate were not influenced to a clinically relevant extent by the application of the study drug. No deviations from normal could be found in the 12-lead-ECGregistrations. The following deviations from protocol were noted: • although not required by the protocol, drop out subject 09 was replaced by subject 19; subject 19 received the treatments in the sequence 'intravenous - oral' and not in the sequence 'oral - intravenous', as did drop out subject 09. Therefore, of the 18 evaluable cases 8 subjects were treated in the sequence 'oral- intraven-
ous' while 10 subjects were treated in the sequence 'intravenous - oral'. • Cmax and tmax were calculated from the individually fitted curves and not from the individually measured data. The moxonidine plasma and urine concentrations were determined by a validated GC/MS method. The results are summarized in Tables II, ill and IV and Figures 1 and 2. Among others, the phannacokinetic parameters calculated (see Table I) included Cmax , lmax, AUC(~Tlast), AUC(~oo), 11/2 U and Ae(24h). The mean areas under the plasma concentration/time curves (AUC(~Tlast» were calculated as 3438 ± 962 pg.hlml for oral administration and 3855 ± 1157 pg.hlml for intravenous administration. The corresponding areas extrapolated to infinity (AUC(~oo» were 3674 ± 1009 pg.hlml for the oral preparation and 4198 ± 1205 pg.hlml for the infusion solution. Mean peak plasma concentrations of 1495 ± 646 pg/ml (oral) and 3965 ± 1342 pg/ml (i.v.) were reached at an average time of 0.56 ± 0.28 h after drug administration for the tablet and at 0.17 ± 0.01 h after start of the infusion (i.e. at the end of infusion). The mean terminal half-lives tl/2 /...2 accounted for 1.98 ± 0.68 h (tablet) and 2.18 ± 0.44 h (infusion). From the urine collected, the renally excreted amounts of unchanged moxonidine during the first 24 h following drug administration (Ae(24h» were 102 ± 26 J.1g or 51 ± 13% after oral .and 122 ± 33 J.1g or 61 ± 16% after intravenous treatment Comparing the bioavailability of the tablet to the bioavailability of the infusion (= 100%), the tablet
157
R. Theodor et 01., Absolute bioavailability ofmoxonidine Table II : Pharmacokinetic parameters of moxonidine after oral and intravenous administration (n = 18) Parameter
ti/2 a
Unit
Oral administration arith. mean ± SD
h
0.353 ± 0.454
Intravenous administration arith. mean ± SD
tI/2Al
h
0.099 ± 0.086*
ti/2 '}.2
h
1.98 ± 0.68
0.074 ± 0.042* 2.18± 0.44
t max
h
0.56 ±0.28
0.17 ± 0.01
C max
pglml
1495 ± 646
3965 ± 1342
AUC(
Absolute bioavailability of moxonidine 2
1
R. THEODORt, H.-I. WEIMANN , W. WEBER and K. MICHAELIS 1 1 LAB. GmbH & Co, Neu-Ulm, Germany 2 Kali-Chemie Pharma GmbH, Hannover, Germany
Receivedfor publication: October 1, 1990 Keywords: Moxonidine, human pharmacokinetics, absolute bioavailability, healthy volunteers
SUMMARY In a randomized 2-way cross-over study with eighteen healthy male volunteers, two moxonidine preparations (tablets, treatment A vs. intravenous solution, treatment B) were tested to investigate absolute bioavailability and pharmacokinetics of moxonidine. The preparations were administered as single doses of 0.2 mg; prior to and up to 24 h after administration blood samples were collected and the plasma moxonidine concentrations determined. Urine samples were collected prior to and at scheduled intervals up to 24 h after administration for the determination of unchanged moxonidine. Moxonidine plasma and urine concentrations were determined by a validated gas chromatographic/mass spectrometric method with negative ion chemical ionization. The mean areas under the plasma concentration/time curves were calculated as [mean ± standard deviation] 3438 ± 962 pg.h1ml (AUC(~T1Mt» and 3674 ± 1009 pg.h1ml (AUC(~oo» for treatment A; 3855 ± 1157 pg.h1ml (AUC(~Tlast» and 4198 ± 1205 pg.h1ml (AUC(O-t oo for treatment B. Mean peak plasma concentrations of 1495 ± 646 pglml were attained at 0.56 ± 0.28 h after oral treatment, mean peak plasma concentrations after intravenous treatment reached 3965 ± 1342 pglml at 0.17 ± 0.01 h (= coinciding with end of infusion). The mean terminal half-lives of moxonidine were derived as 1.98 h after administration of the tablet and as 2.18 h after infusion. The amounts of moxonidine excreted in urine during the 24 h following administration (Ae(24h» in absolute figures and as percentage of the dose administered were 102 ± 26 J.Lg or 51 ± 13% for the tablet and 122 ± 33 J.Lg or 61 ± 16% for the infusion.
»
The relative bioavailability of oral moxonidine (assuming the availability of the i.v. solution to be 100%) was calculated to be 89% or F = 0.89 (AUC(O-tTlast» and 88% or F = 0.88 (AUC(O-too». Taking these results into account, the relative amount of moxonidine excreted in urine of the dose absorbed comes up to approximately 58% for the tablet, which is comparable to an excretion of 61% of the dose administered (= absorbed) after i.v, administration. With the self-evident exception of CIIUlXt statistical testing of pharmacokinetic parameters revealed no significant differences between treatments.
INTRODUCTION Moxonidine, 2-methyl-4-chloro-5-(2-imidazoline-2ylamino)-6-methoxy-pyrimidine, is a new centrally acting antihypertensive agent It is a selective cz-adrenoceptor agonist that differs from other centrally acting a,2-stimulating antihypertensive agents in the following properties (1-3): Please send reprint requests to : Dr. H.-I. Weimann, Kali-Chemie Pharma GmbH, Hans-Beckler-Allee 20, D-3000 Hannover, Germany
• high a,z/a,I-selectivity ratio, • high selectivity for presynaptic cz-receptors. • full intrinsic activity at the cz-receptors. These characteristics have been suggested to be the main factors responsible for the reported lower incidence of side effects of moxonidine compared to the partial a,2-agonistclonidine-HCI (2). Following oral administration, 80-90% of the dose is absorbed from the gastrointestinal tract (4). After a single oral dose of 0.2 mg moxonidine, peak. plasma levels of 1.3 ± 0.3 ng/ml were reached after 0.7 ± 0.4 h. The drug is eliminated with a terminal half-life of
154
Eur. J. Drug Metab. Pharmacokinet., 1991, No.2
2.1 ± 0.6 h. No statistically significant alterations are reported after repeated dosing (5). About 7% of moxonidine is bound to human plasma proteins. About 10% of moxonidine is metabolized to 4,5-dehydromoxonidine and, by opening of the imidazoline ring, to a guanidine derivative. These metabolites show less than 10% and 1%, respectively, of the blood pressure reducing potency of the parent drug. The elimination of moxonidine and its metabolites is predominantly by the renal route. Over 90% of the applied radioactivity is eliminated in the first 24 h after administration, about 1% in feces (4). Multiple oral dosing in hypertensive patients resulted in a persistent blood pressure reduction, supine as well as standing (6). After treatment with a mean daily dose of 0.3 mg of moxonidine, blood pressure was strongly reduced during the first three weeks, after this decreasing only slightly. After one year treatment, mean supine systolic and diastolic blood pressure reduction was -24/-18 mmHg (7). Heart rate remained almost uninfluenced. Biochemical and hematological parameters (mean values) did not change significantly (7). The hypotensive effect of moxonidine is mainly caused by a decrease in peripheral resistance, while cardiac output remains unchanged (8). This finding corresponds to the observation, that moxonidine showed very good efficacy in patients older than 60 years of age (7). The most common adverse drug reactions are dryness of mouth and fatigue. Other observations had been, for example, headache, vertigo, nervousness, nausea, orthostatic dysregulations. Withdrawals due to adverse drug reactions were reported in about 2% of participants. Serious adverse drug reactions have not been observed. Contraindication for a treatment with moxonidine is a sick sinus syndrome. The recommended dose range is 0.2 to 0.6 mg/day, given once daily or b.i.d.. The highest dose of 2.0 mg/day moxonidine revealed no serious adverse drug reactions (ADR) (7).
e
The only data available on absolute bioavailability were derived from a study with 4C]-radiolabelled moxonidine, performed in 6 volunteers in 1986 (4). At that time, no sophisticated analytical methods for unchanged moxonidine, such as the GC/MS method used for the present study were available. The aim of this study was to detennine absolute bioavailability and pharmacokinetics of moxonidine in man following oral and intravenous administration of 0.2 mg to healthy male volunteers under single dose conditions using state-of-the-art technology.
MATERIALS AND METHODS Study design The study was performed as an open, randomized, single-dose, two-period crossover study. The study periods were separated by a wash-out phase of five days. After an overnight fasting period the participants received a single dose of 0.2 mg moxonidine via the oral or intravenous route in a randomized sequence order. The first meal was served 4 h after drug administration. During each study session the volunteers were confmed for two nights and one day (observation period approximately 36 h). When not confmed to the study site, the volunteers maintained their normal daily activity, but were instructed to report any event, which might have an influence on the study performance. All adverse events or adverse drug reactions occurring during the study were documented.
Subjects Nineteen healthy male volunteers between 20 and 48 years of age were enrolled in the study. Eighteen of them completed the study, one subject dropped out for personal reasons after period 1. The mean age ± standard deviation of the subjects completing the study was 31.7 ± 9.5 years, the mean body weight was 74.8 ± 5.6 kg, the mean height was 179.3 ± 7.4 em. A prestudy and poststudy examination was performed including physical examinations and extensive laboratory screenings. Written voluntary consent was obtained from all subjects. Prior to initiation, the study had been approved by an independent ethical committee. During a two week period preceding the study and for the entire duration of the study no drug treatment other than the test preparations were allowed. Furthermore, the consumption of caffeinated or alcoholic food or beverages as well as extensive physical activities were not allowed during periods of confinement to the study site.
Drug application Moxonidine was given as 0.2 mg tablets (batch 051 G, treatment A) or as an intravenous solution with a strength of 0.4 mg/2 ml (batch 059 G, treatment B). The dose was 1 tablet or 1 ml of the solution. The
R. Theodor et al., Absolute bioavailability of'moxonidine tablet was taken with 200 ml of water in an upright position. The infusion solution was prepared by diluting 2 ml (= 0.4 mg) of the moxonidine solution with physiological saline up to a volume of 20 ml. Ten ml of this solution (= 0.2 mg of moxonidine) were administered in a sup-ine position by means of an infusion pump (Perfusor®, Braun-Melsungen) at a constant infusion rate of 1 ml/min over a period of 10 min. For this purpose an indwelling catheter was used, which was placed on the ann contralateral to the one used for blood samplings.
Blood samples and urine collection Blood samples of 10 ml each were collected by an indwelling catheter or by individual venipuncture with a steel canula into lithium-heparinized Sarstedt Monovettes® (Sarstedt, Niirmbrecht, Germany) at the following times: • oral application: predose (before drug administration) and 10, 20, 30, 45, 60, 90 min and 2, 2.5, 3, 3.5,4,6, 8, 10, 12, 14, 16 and 24 h after drug administration; • intravenous application: predose (before drug administration) and 5,10, 15,20,30,45,60, 90 min and 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 14, 16 and 24 h after start of infusion. Directly after collection, blood samples were centrifuged for 15 min at +4°C at 3000 g and the resultant plasma supernatant stored at -20°C until analysis. Urine samples were collected prior to dosing and during the following intervals thereafter for both routes of administration: • predose (before drug administration) andfrom 0-3, 3-6, 6-9, 9-12 and 12-24 h afterwards. At the end of each interval the volunteers were required to empty their bladder. The volume and pH of each sample were measured and documented. An aliquot of 50 ml was taken and stored at -20°C until analysis.
Safety parameters Blood pressure and heart rate were monitored by a sphygmomanometric semiautomatic device (BOSO Digital IT S, Bosch + Sohn) at the following times, (after the blood sample had been withdrawn, if coinciding): • oral application: predose and 1,2,4,8 and 12 h;
155
• intravenous application: predose and 10,20, 40 min and 1, 1.5,2,4,8 and 12 h. A 12-lead-ECG was registered prior to the drug applications and during the poststudy examination. Adverse events and adverse drug reactions were evaluated by open questioning or by spontaneous reports of the volunteers. On the evening prior to the drug applications a short interview with a physician was performed,
Analytical approach For the quantitative determination of moxonidine in plasma and urine, a validated gas chromatographic} mass spectrometric method (GC/MS) with negative ion chemical ionization was used (9).
Calculation of pharmacokinetic parameters Phannacokinetic parameters were derived from the analytical data by means of the TOPFlT computer program (Dr Karl Thomae GmbH, Biberach/RiB, Germany) using an open two-compartment model with lag time. The oral data of subjects 15 and 16 were evaluated with an open one-eompartment model with lag time. The parameter Ae(24h) was assessed directly from the renal excretion data (see Table I).
Statistical analysis After logarithmic transformation, the parameters Cmax, AUC(~Tlast), AUC(~oo), tlfl 1..2 and Ae(24h) were analyzed according to the Grizzle model for cross-over trials without interaction between period and treatment The two one-sided t-tests procedure (10) for equivalence within the (80%, 125%) range and the two-sided t-test for treatment difference were applied. Conventional 90% and 95% confidence intervals were calculated.
RESULTS AND DISCUSSION A total of 19 volunteers was enrolled into this study. Eighteen of them completed the trial in accordance with the protocol. One subject dropped from the study due to personal reasons after completion of period 1.
Eur. J. Drug Metab. Pharmacokinet., 1991, No.2
156
Table I : Pharmacokinetic parameters derived from the analytical data Parameter
Unit
tin. a
h
Definition Absorption half-life (oral dosing only)
tIn. 1..1
h
Distribution half-life
tin. A.2
h
Termimal half-life
tmax
h
Peak plasma concentration of the fitted curve
C max
pglml
Time to peak plasma concentration of the fitted curve
AUC«HTIlm)
pg.hJml
AUC until last quantified sample using the trapezoidal rule with lag-time
AUC«Hoo)
pg.hJml
AUC of the fitted curve until infinity
Vd
lIkg
Volume of distribution in the central compartment
Vas
lIkg
Volume of distribution in steady state
CLtot
mlIminlkg
Total clearance
MIT
h
Mean transit time
Ae(24h)
J.Lg
Amount excreted
Ae(24h)
% of dose
Amount excreted
Therefore, 18 completed cases could be taken into the evaluation. After oral application, 7 subjects reported adverse drug reactions, mild in intensity; the symptoms had been headache and tiredness. After intravenous application, 3 subjects reported adverse drug reactions, mild in intensity; the symptoms had been headache, tiredness and dryness of mouth. None of the adverse drug reactions needed treatment, the drug relation was rated possible (= 2) in each case according to a five-step rating scale (Adverse Event Form, Kali Chemie). A relevant difference between the treatments could not be found regarding the quality of adverse drug reactions. The poststudy examination revealed no relevant changes during the physical and laboratory examinations as compared to the prestudy examination. Blood pressure and heart rate were not influenced to a clinically relevant extent by the application of the study drug. No deviations from normal could be found in the 12-lead-ECGregistrations. The following deviations from protocol were noted: • although not required by the protocol, drop out subject 09 was replaced by subject 19; subject 19 received the treatments in the sequence 'intravenous - oral' and not in the sequence 'oral - intravenous', as did drop out subject 09. Therefore, of the 18 evaluable cases 8 subjects were treated in the sequence 'oral- intraven-
ous' while 10 subjects were treated in the sequence 'intravenous - oral'. • Cmax and tmax were calculated from the individually fitted curves and not from the individually measured data. The moxonidine plasma and urine concentrations were determined by a validated GC/MS method. The results are summarized in Tables II, ill and IV and Figures 1 and 2. Among others, the phannacokinetic parameters calculated (see Table I) included Cmax , lmax, AUC(~Tlast), AUC(~oo), 11/2 U and Ae(24h). The mean areas under the plasma concentration/time curves (AUC(~Tlast» were calculated as 3438 ± 962 pg.hlml for oral administration and 3855 ± 1157 pg.hlml for intravenous administration. The corresponding areas extrapolated to infinity (AUC(~oo» were 3674 ± 1009 pg.hlml for the oral preparation and 4198 ± 1205 pg.hlml for the infusion solution. Mean peak plasma concentrations of 1495 ± 646 pg/ml (oral) and 3965 ± 1342 pg/ml (i.v.) were reached at an average time of 0.56 ± 0.28 h after drug administration for the tablet and at 0.17 ± 0.01 h after start of the infusion (i.e. at the end of infusion). The mean terminal half-lives tl/2 /...2 accounted for 1.98 ± 0.68 h (tablet) and 2.18 ± 0.44 h (infusion). From the urine collected, the renally excreted amounts of unchanged moxonidine during the first 24 h following drug administration (Ae(24h» were 102 ± 26 J.1g or 51 ± 13% after oral .and 122 ± 33 J.1g or 61 ± 16% after intravenous treatment Comparing the bioavailability of the tablet to the bioavailability of the infusion (= 100%), the tablet
157
R. Theodor et 01., Absolute bioavailability ofmoxonidine Table II : Pharmacokinetic parameters of moxonidine after oral and intravenous administration (n = 18) Parameter
ti/2 a
Unit
Oral administration arith. mean ± SD
h
0.353 ± 0.454
Intravenous administration arith. mean ± SD
tI/2Al
h
0.099 ± 0.086*
ti/2 '}.2
h
1.98 ± 0.68
0.074 ± 0.042* 2.18± 0.44
t max
h
0.56 ±0.28
0.17 ± 0.01
C max
pglml
1495 ± 646
3965 ± 1342
AUC(
