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Eur J Clin Pharmacol (1993) 44:575-578 P es eceSe@ © Springer-Verlag 1993 Pharmacokinetics of pantoprazole following single intravenous and oral administration to healthy male subjects M. A. Pue 1 , J. Laroche 2, I. Meineke 3'*, and C. de Mey s'** SmithKline Beecham, Department of Drug Metabolism and Pharmacokinetics, Welwyn, UK 2SmithKline Beecham, Department of Clinical Pharmacology Operations, Statistics, Welwyn, UK s SK&F-Institute for Applied Clinical Pharmacology, G6ttingen, Germany Received: April 8, 1992/Accepted in revised form: February 16, 1993 Summary. The plasma pharmacokinetics of pantoprazole have been investigated following single intravenous infu- sion and single oral administration at a dose of 40 mg to 12 healthy male subjects in a randomised cross-over study. Both treatments were generally well tolerated and no relevant compound-related adverse events were noted. The plasma pharmacokinetics of pantoprazole following intravenous infusion in this group of subjects were charac- terised by a total plasma clearance of 0.13 1. h -1. kg ~and apparent terminal elimination half-life 1.9 h. The appar- ent volume of distribution estimated at steady state (0.17 1.kg -1) was compatible with the localization of a major fraction of the compound in extracellular water. Following oral administration as an enteric-coated tablet formulation, a variable onset of absorption was followed by rapid attainment of maximum plasma concentrations of pantoprazole. Pantoprazole was well absorbed following oral admin- istration; the absolute systemic bioavailability of the com- pound was estimated as 77 % (95 % CI, 67 to 89 %). Key words: Pantoprazole; pharmacokinetics, bioavail- ability Pantoprazole (sodium 5-difluoromethoxy-2- [(3,4- dimethoxy-2-pyridylmethyl) sulphinyl]-lH-benzimidazo- lide, SK&F 96022-Z, BY 1023) is a potent inhibitor of the gastric parietal cell H+/K+-ATPase [1], under develop- ment for the treatment of disease states associated with excessive gastric acid secretion. The compound produces dose-dependent and long-lasting inhibition of pentagas- trin-stimulated gastric acid output when administered as single intravenous infusions to healthy male subjects [2]. Since pantoprazole, in common with other substituted benzimadazoles [3], is acid-labile, the oral formulation * Present address: Department of Clinical Pharmacology, University of G6ttingen, D-37075 G(3ttingen, Germany ** Present address: Center for Cardiovascular Pharmacology, Alwi- nenstrasse 16, D-65189 Wiesbaden, Germany currently being used for clinical trials consists of enteric- coated tablets in a gelatin capsule. The aim of this study was to describe the plasma phar- macokinetics of pantoprazole following single intraven- ous constant rate infusion and oral administration as an enteric-coated formulation to healthy male subjects at a dose of 40 mg. Subjects and methods Twelve male subjects (19 to 29 y, mean body weight 74 kg) who on the basis of extensive medical and laboratory screening were judged to be healthy, participated in this study. The study was con- ducted in agreement with the declaration of Helsinki [Venice Amendment 1983] and the protocol was reviewed and approved by an independent Frythe Ethics Committee. The subjects were fully informed about the nature of the study and the medication and they confirmed their consent in writing and in the presence of a witness. Table L Individual pharmacokinetic parameter estimates for pan- toprazole following single intravenous infusion to 12 healthy male subjects at a dose of 40 mg Subject Cm~ tl/2 Vss CL MRT (gg. ml-~) (h) (1. kg -~) (1. h ~.kg-z) (h) 1 4.24 0.80 0.15 0.196 0.79 2 5.57 2.5 0.16 0.055 2.9 3 4.26 0.98 0.15 0.164 0.93 4 4.31 0.95 0.15 0.138 1.1 5 4.89 5.1 0.18 0.027 6.5 6 7.05 1.8 0.12 0.073 1.7 7 4.61 2.9 0.23 0.146 1.5 8 3.21 1.9 0.21 0.193 1.1 9 3.99 1.3 0.20 0.195 1.0 10 3.74 0.95 0.17 0.150 1.1 11 4.99 1.7 0.15 0.075 2.0 12 4.53 2.2 0.19 0.130 1.5 Mean 4.62 1.9 0.17 0.129 1.9 SD 0.98 1.2 0.03 0.058 1.6 Median 4.42 1.7 0.18 0.142 1.3 Min 3.21 0.80 0.12 0.027 0.79 Max 7.05 5.1 0.23 0.196 6.5

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Page 1: Pharmacokinetics of pantoprazole following single intravenous and oral administration to healthy male subjects

Eur J Clin Pharmacol (1993) 44:575-578

P es eceSe@ © Springer-Verlag 1993

Pharmacokinetics of pantoprazole following single intravenous and oral administration to healthy male subjects M. A. Pue 1 , J. Laroche 2, I. Meineke 3'* , and C. de Mey s'**

SmithKline Beecham, Department of Drug Metabolism and Pharmacokinetics, Welwyn, UK 2 SmithKline Beecham, Department of Clinical Pharmacology Operations, Statistics, Welwyn, UK s SK&F-Institute for Applied Clinical Pharmacology, G6ttingen, Germany

Received: April 8, 1992/Accepted in revised form: February 16, 1993

Summary. The plasma pharmacokinetics of pantoprazole have been investigated following single intravenous infu- sion and single oral administration at a dose of 40 mg to 12 healthy male subjects in a randomised cross-over study.

Both t reatments were generally well tolerated and no relevant compound-rela ted adverse events were noted. The plasma pharmacokinet ics of pantoprazole following intravenous infusion in this group of subjects were charac- terised by a total plasma clearance of 0.13 1. h -1. kg ~ and apparent terminal elimination half-life 1.9 h. The appar- ent volume of distribution estimated at steady state (0.17 1.kg -1) was compatible with the localization of a major fraction of the compound in extracellular water. Following oral administration as an enteric-coated tablet formulation, a variable onset of absorption was followed by rapid at tainment of maximum plasma concentrations of pantoprazole.

Pantoprazole was well absorbed following oral admin- istration; the absolute systemic bioavailability of the com- pound was estimated as 77 % (95 % CI, 67 to 89 %).

Key words: Pantoprazole; pharmacokinetics, bioavail- ability

Pantoprazole (sodium 5-difluoromethoxy-2- [(3,4- dimethoxy-2-pyridylmethyl) sulphinyl]-lH-benzimidazo- lide, SK&F 96022-Z, BY 1023) is a potent inhibitor of the gastric parietal cell H+/K+-ATPase [1], under develop- ment for the t reatment of disease states associated with excessive gastric acid secretion. The compound produces dose-dependent and long-lasting inhibition of pentagas- trin-stimulated gastric acid output when administered as single intravenous infusions to healthy male subjects [2]. Since pantoprazole, in common with other substituted benzimadazoles [3], is acid-labile, the oral formulation

* Present address: Department of Clinical Pharmacology, University of G6ttingen, D-37075 G(3ttingen, Germany ** Presen t address: Center for Cardiovascular Pharmacology, Alwi- nenstrasse 16, D-65189 Wiesbaden, Germany

currently being used for clinical trials consists of enteric- coated tablets in a gelatin capsule.

The aim of this study was to describe the plasma phar- macokinetics of pantoprazole following single intraven- ous constant rate infusion and oral administration as an enteric-coated formulation to healthy male subjects at a dose of 40 mg.

Subjects and methods

Twelve male subjects (19 to 29 y, mean body weight 74 kg) who on the basis of extensive medical and laboratory screening were judged to be healthy, participated in this study. The study was con- ducted in agreement with the declaration of Helsinki [Venice Amendment 1983] and the protocol was reviewed and approved by an independent Frythe Ethics Committee. The subjects were fully informed about the nature of the study and the medication and they confirmed their consent in writing and in the presence of a witness.

Table L Individual pharmacokinetic parameter estimates for pan- toprazole following single intravenous infusion to 12 healthy male subjects at a dose of 40 mg

Subject Cm~ tl/2 Vss CL MRT (gg. ml-~) (h) (1. kg -~) (1. h ~. kg-z) (h)

1 4.24 0.80 0.15 0.196 0.79 2 5.57 2.5 0.16 0.055 2.9 3 4.26 0.98 0.15 0.164 0.93 4 4.31 0.95 0.15 0.138 1.1 5 4.89 5.1 0.18 0.027 6.5 6 7.05 1.8 0.12 0.073 1.7 7 4.61 2.9 0.23 0.146 1.5 8 3.21 1.9 0.21 0.193 1.1 9 3.99 1.3 0.20 0.195 1.0

10 3.74 0.95 0.17 0.150 1.1 11 4.99 1.7 0.15 0.075 2.0 12 4.53 2.2 0.19 0.130 1.5

Mean 4.62 1.9 0.17 0.129 1.9 SD 0.98 1.2 0.03 0.058 1.6 Median 4.42 1.7 0.18 0.142 1.3 Min 3.21 0.80 0.12 0.027 0.79 Max 7.05 5.1 0.23 0.196 6.5

Page 2: Pharmacokinetics of pantoprazole following single intravenous and oral administration to healthy male subjects

576

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Fig. 1 a, b. Individual plasma con- centration-time profiles for pan- toprazole following (a) single intravenous infusion and (b) single oral administration (enteric-coated tablet formula- tion) to 12 healthy male subjects at a dose of 40 rag. Maximum (Subject 5 - • - ) and minimum (Subject 8 , - • -) profiles are shown in detail

Enteric-coated tablets of 20 mg pantoprazole and a solution of pan- toprazole for parenteral administration were supplied by the SmithKline Beecham Department of Pharmaceutical Develop- ment, Welwyn Garden City, England. The parenteral dose was ad- ministered via a forearm vein as a constant rate intravenous infu- sion of 40 mg over 15 rain as a side-line to a main line of isotonic saline (100 ml. h 1). The oral dose was administered as a single oral dose of 2 x 20 mg tablets in a gelatin capsule with 200 ml water. The 2 treatments were randomly allocated in a period-balanced cross- over study. The subjects fasted overnight prior to both dose admin- istrations and up to 5 h post-dose. A series of blood samples was collected from each subject up to 12 h post-dose. Blood samples were collected into heparinised tubes and were centrifuged imme- diately. Plasma samples were separated and stored frozen ( - 20°C) until analysis.

Plasma concentrations of pantoprazole were determined using a specific high performance chromatographic (HPLC) method with UV detection [Lundberg DE, et al. (1991) unpublished data]. The limit of quantification for the assay was 0.01 gg. ml 1.

The maximum plasma concentration of pantoprazole (Cmax) and the time at which this maximum occurred (tmax) were obtained by vi- sual inspection of the individual pantoprazole plasma concentra- tion-time data. The area under the individual pantoprazole plasma concentration-time data up to the last time point at which pantopra- zole was quantifiable [AUe(0-tlast)] was estimated using a combina- tion of linear and log trapezoidal methods [4]. The apparent terminal elimination rate constant (k) was obtained by log-linear least squares regression analysis of the data points estimated by visual in- spection to be on the terminal log-linear decline of the pantoprazole plasma concentration-time profiles. The apparent terminal elimina- tion half-life (tv2) was calculated as ln2/k. The area under the panto- prazole plasma concentration-time curves extrapolated to infinity [AUC] was estimated as the sum of AUC(0-tLast) and C(t~ast)/k, where C(tlast) is the pantoprazole plasma concentration at time tlas~, esti- mated from the regression analysis. The area under the statistical first moment curve up to the last time point at which pantoprazolc was quantifiable [AUMC(0-tI~t)] was calculated in a similar manner using the combined linear/log trapezoidal methods. This area extra- polated to infinity [AUMC(0-o~)] was estimated as the sum of AUMC(0-h~s~), t~ast*e(tl~t)/k and C(qa~)/k 2. The mean residence time (MRT) for each subject was calculated as the ratio of AUMC(0-~) to AUC(0-~), corrected for the infusion time for the intravenous ad- ministration. For the intravenous dose only, the total plasma clear- ance (CL) and the apparent volume of distribution at steady state (Vss) for pantoprazole were calculated for each subject as the ratio of

the intravenous dose to AUC and the product of CL and MRT after intravenous administration, respectively. The absolute bioavail- ability was calculated as the ratio of AUC values following oral ad- ministration to AUC values following intravenous administration for each subject, the same dose having been administered by the two routes and assuming constant clearance for pantoprazole for the two routes of administration. The average absolute bioavailability of pantoprazole (f~bs) from the oral formulation used in this study was estimated by the geometric mean of the individual ratios.

Log-transformed AUC values were analysed by analysis of vari- ance (ANOVA) and the model fitted included effects for subject, se- quence, period and treatment. The 95 % confidence interval (95 % CI) for the mean difference between the two treatments was esti- mated using the residual variance from the regression analysis. The difference and 95 % CI on the log-scale were then back-transformed to give ratios on the original scale. The residual coefficient of vari- ation for log-transformed AUC was calculated using the formula for lognormal distribution, CVr~sid% = [exp(residual variance)-l]l/2 x 100%

Results

The two dose t r e a tme n t s were genera l ly well t o l e r a t e d and no adverse c o m p o u n d - r e l a t e d events were noted . A l l 12 subjects c o m p l e t e d the s tudy accord ing to the p ro- tocol .

Fo l lowing single in t r avenous infusion of p a n t o p r a z o l e at a dose of 40 mg a d m i n i s t e r e d over 15 min, p l a sma con- cen t ra t ions of p a n t o p r a z o l e at the end of the infusion r anged f rom 3.21-7.05 gg-m1-1 in the 12sub jec t s (Table 1). Therea f t e r , p a n t o p r a z o l e p l a s m a concent ra - t ions dec l ined and were gene ra l ly close to o r be low the l imit of quan t i f i ca t ion for the assay (0.01 gg . m l - 2) by 12 h pos t -dose (Fig. 1). T h e a p p a r e n t t e r m i n a l e l imina t ion half-l ife es t imates in 11 of the 12 subjects r anged f rom 0 .8- 2.9 h, wi th one subjec t (Subjec t 5) having a much g r ea t e r half l ife va lue of 5.1 h (Table 1).

The m e a n (SD) a p p a r e n t vo lume of d i s t r ibu t ion at s t eady-s ta te for p a n t o p r a z o l e in the 12 subjects was 0.17 (0.03) 1. kg-2. Es t ima te s of the to ta l sys temic c lea rance

Page 3: Pharmacokinetics of pantoprazole following single intravenous and oral administration to healthy male subjects

577

and MRT for pantoprazole in 11 of the 12 subjects ranged from 0.055 to 0.196 1 .h - l .kg -1 and 0.79-2.9 hours, re- spectively (Table1). Subject 5 had lower clearance (0.027 1- h - i. kg - a ) and higher MRT (6.5 h) estimates than the other subjects in the study.

Following oral administration, individual pantopra- zole plasma concentration-time profiles were charac- terized by a variable onset of absorption followed by rapid attainment of Cmax (Fig. 1). Maximum plasma concentra- tions of pantoprazole ranged from 1.11-3.12 gg. ml- 1 and were achieved at 2-4 h post-dose (Table 2). Estimates of the apparent terminal elimination half-life following oral administration were similar to those achieved after the in- travenous dose (Table 1). Values of MRT following oral administration were approximately 3-times longer than after intravenous infusion due to the time-lag for the onset of absorption to occur from the enteric-coated tablet for- mulation.

The absolute bioavailability of pantoprazole was esti- mated as 77 % (Table 3). The 95 % confidence interval for this parameter was 67-89 % and the within-subject coeffi- cient of variation was 15 %.

Discussion

The intravenous pharmacokinetics of pantoprazole fol- lowing a dose of 40 mg to the healthy male subjects in this study were characterized by an apparent terminal elimi- nation half-life of approximately 2 h and a total systemic plasma clearance of 0.13 1. h- 1. kg- z. The blood to plasma ratio for pantoprazole has been estimated from in vitro studies to be approximately 0.55 over the concentration range observed in this study [D.Mason, S.Roffey, R J. Wood, R. Griffiths, SB, unpublished data.] Thus, the total blood clearance for pantoprazole, approximately 0.25 1. h 1. kg- 1, equates to approximately 15-20 % of he- patic blood flow in man.

Preliminary data indicate that renal excretion is not a significant route of elimination of pantoprazole in man and, therefore, total blood clearance equates essentially to metabolic (hepatic) clearance. The hepatic extraction ratio, ER, for pantoprazole can be estimated using the well-stirred model of hepatic extraction [5] and a fraction unbound in blood of 0.075 [S.Roffey, D.Knowler, P. J. Wood, R. Griffiths, SB, unpublished data] to be ap- proximately 0.154).2. Thus, pantoprazole is a low hepatic extraction compound in man and, as such, bioavailability of the compound would not be expected to be severely compromised due solely to first pass hepatic elimination. The maximum theoretical oral bioavailability of panto- prazole can be estimated from (1-ER)x 100 [5] as ap- proximately 80-85 %. This is similar to the mean bio- availability estimate of 77% for pantoprazole in this study. These data, together with the relatively small degree of variability in the bioavailability point estimate as reflected by the 95 % confidence interval and within- subject coefficient of variation of 15 %, indicate that the enteric coated tablet formulation is an excellent solid oral dose form for the therapeutic evaluation of panto- prazole in man.

Table 2. Individual pharmacokinetic parameter estimates for pan- toprazole following single oral administration as an enteric-coated tablet formulation to 12 healthy male subjects at a dose of 40 mg

Subject Cma x tmax t~/2 MRT (gg. ml- 1) (h) (h) (h)

1 1.97 2.0 0.88 2.7 2 2.79 2.5 3.2 6.2 3 1.13 3.0 0.82 3.5 4 2.82 3.0 1.1 4.1 5 3.12 4.0 4.8 1.0.2 6 2.41 2.0 1.6 3.6 7 2.36 3.0 2.2 4.0 8 1.11 2.0 0.79 2.8 9 1.51 3.0 1.2 3.9

10 1.59 2.5 1.3 3.7 11 2.27 3.0 3.9 5.3 12 1.98 2.5 1.1 3.5

Mean 2.09 - 1.9 4.5 SD 0.66 - 1.3 2.0 Median 2.13 2.8 1.2 3.8 Min 1.11 2.0 0.79 2.7 Max 3.12 4.0 4.8 10.2

Table 3. Estimation of absolute bioavailability of pantoprazole fol- lowing single intravenous infusion and oral administration (enteric- coated tablet formulation) to 12 healthy male subjects at a dose of 40 mg

Subject AUC (~tg. h. ml-l)

IV PO PO/IV

1 2.65 2.15 0.81 2 9.58 11.3 1.18 3 3.06 1.88 0.62 4 3.88 4.00 1.03 5 20.9 19.7 0.94 6 8.47 5.19 0.61 7 4.15 2.83 0.68 8 2.47 1.51 0.61 9 2.70 1.89 0.70

10 3.56 2.84 0.80 11 7.39 5.55 0.75 12 4.67 3.51 0.75

Geometric mean 0.77 95 % CI 0.67, CV residual = 15 %

0.89

The time to achieve maximum plasma concentrations of pantoprazole following administration of the enteric- coated tablets used in this study showed relatively little variability (2-4 h post-dose) between the subjects studied. The ranges of values for Cmax and tmax are probably a result of the use of an enteric-coated formulation, but the degree of variability in these and the other pharmacokinetic par- ameters is small compared with that reported for enteric- coated formulations of the structurally-related benzimid- azole sulphoxide, omeprazole. The absorption of omepra- zole from an enteric-coated granule formulation has been reported as highly variable and unpredictable following single and multiple dose administration to healthy male subjects at a dose of 30 and 60 mg [6]. Values of tmax and Cmax for omeprazole, for example, covered 6-fold and 5-fold ranges, respectively, following single oral adminis- tration at a dose of 30 mg.

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The mean apparent volume of distribution at steady state for pantoprazole in the subjects in this study was e s - t imated as 0.17 1-kg-1. Omeprazole has been repor ted as having a very similar apparent volume of distribution at steady state in healthy volunteers (0.24 1-kg -1) [7]. These data indicate that both compounds undergo limited tissue distribution in man and the Vss values are compatible with localization of a major fraction of the compounds in ex- tracellular water.

Estimates of A U C values for one subject in the pre- sent study (Subject 5) were 4-5 times higher than the mean values for the remaining subjects following in- travenous and oral administration (Table 3). This subject had the lowest total plasma clearance (0.03 1. h -~. kg-1) following intravenous administration. The lower clear- ance, without any noticeable difference in Vss, for this subject compared with the other subjects in the study was reflected in a prolonged apparent terminal halflife esti- mate (5.1 h) for this individual. It has been reported that a few individuals exhibit a lower metabolic clearance (higher systemic exposure) of omeprazole than the ma- jority of healthy volunteers [8], and this polymorphism co-segregates with S-mephenytoin hydroxylase pheno- type [9]. It was not possible to retrospectively phenotype the volunteers in the present study. Thus, it is presently unclear whether Subject 5 in this study represents a dis- tinct sub-population of individuals for the metabolism of pantoprazole or how this decreased capacity relates to the ability to metabolise other drugs, including those showing genetic polymorphism.

In summary, the results of this study indicate that pan- toprazole was rapidly absorbed with a high oral bioavail- ability f rom the enteric-coated tablet formulation. The in- travenous pharmacokinetics of the compound indicate that pantoprazole is a low hepatic extraction compound with a relatively small volume of distribution and low total plasma clearance.

References

1. Simon WA, Keeling DJ, Laing SM, Fallowfield C, Taylor AG (1990) BY 1023/SK&F 96022: biochemistry of a novel (H + + K ÷)- ATPase inhibitor. Biochem Pharmaco139:1799-1806

2. Simon B, Mtiller R Bliesath H, Ltihmann R, Hartmann M, Huber R, Wurst W (1990) Single intravenous administration of the H ÷ ,K÷-ATPase inhibitor BY 1023/SK&F 96022 - inhibition of pentagastrin-stimulated gastric acid secretion and pharmaco- kinetics in man. Aliment Pharmacol Ther 4:239-245

3. Figala V, Klemm K, Kohl B, Kriiger U, Rainer G, Schaefer H, Senn-Bilfinger J, Sturm E (1986) Acid activation of (H + -K +)-AT- Pase inhibiting 2-(2-pyridylethyl-sulphinyl)benzimidazoles: isola- tion and characterisation of the thiophilic 'active principle' and its reactions. J Chem Soc Chem Commun 125-127

4. Chiou WL (1978) Critical evaluation of the potential error in pharmacokinetic studies of using the linear trapezoidal rule method for the calculation of the area under the plasma level-time curve. J Pharmacokinet Biopharm 6:539-546

5. Rowland M, Tozer TN (1989) Clinical pharmacokinetics: con- cepts and applications. Lea&Febinger, Philadelphia

6. Howden CW, Meredith PA, Forrest JAH, Reid JL (1984) Oral pharmacokinetics of omeprazole. Eur J Clin Pharmaco126: 641- 643

7. Reg~rdh CG, Andersson T, Lagerstr/Sm PO, Lundberg R Skgm- berg I (1990) The pharmacokinetics of omeprazole in humans. A study of single intravenous and oral doses. Ther Drug Monit 12: 163-172

8. Andersson T, Cederberg C, Edvardsson G, Heggeltmd A Lund- borg P (1990) Effect of omeprazole treatment on diazepam plas- ma levels in slow versus normal rapid metabolizers of omeprazole. Clin Pharmacol Ther 47:79-85

9. Andersson T, Reggtrdh CG, Dahl-Puustinen ML, Bertilsson L (1990) Slow omeprazole metabolizers are also poor S-mepheny- toin hyroxylators. Ther Drug Monit 12:415-416

Dr.M.A.Pue SmithKline Beecham Department of Drug Metabolism and Pharmacokinetics The Frythe Welwyn, Herts., AL6 9AR UK