JAC Advance Access originally published online on September 20, 2002
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Journal of Antimicrobial Chemotherapy (2002) 50, 699-706
© 2002 The British Society for Antimicrobial Chemotherapy
Pharmacokinetics of lansoprazole, amoxicillin and clarithromycin after simultaneous and single administration
1 Department of Chest and Infectious Diseases, Hospital Heckeshorn-Zehlendorf, Berlin; 2 Klinikum Benjamin Franklin, Freie Universität Berlin, Berlin, Germany
Received 22 March 2002; returned 14 May 2002; revised 27 June 2002; accepted 9 July 2002
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Abstract |
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In a randomized, double-blind, placebo-controlled, four-way crossover study, possible influences of the triple therapy with amoxicillin, clarithromycin and the proton pump inhibitor lansoprazole on the pharmacokinetics of each of the drugs and the active 14-OH-clarithromycin metabolite were assessed. Twelve Helicobacter pylori-negative healthy male volunteers (age 27 ± 4.3 years; creatinine clearance 7.0 ± 2.0 L/h) were given lansoprazole 30 mg, amoxicillin 1 g and clarithromycin 500 mg, alone and in triple combination. Drug elimination intervals were at least 9 days between the dosing periods. The study medication was administered twice daily for 4 days. On the fifth day of each period, drugs were only given once in the morning, and blood and urine samples were collected for 12 h. The concentrations of the three substances administered, and 14-OH-clarithromycin, were determined by validated HPLC methods. Alterations in the serum kinetics were found for lansoprazole and the active 14-OH-clarithromycin metabolite (all data expressed as mean ± S.D.). For lansoprazole, the elimination half-life (t1/2) was significantly prolonged (1.46 versus 1.7 h, P < 0.05) and the area under the concentration–time curve from 0 to 8 h (AUC0–8) was significantly increased (3.65 versus 4.59 mg·h/L, P < 0.05) by combination of the drugs. For 14-OH-clarithromycin, the peak concentration (Cmax) was 0.95 versus 1.18 mg/L and the AUC from 0 to 12 h (AUC0–12) was 8.3 versus 10.5 mg·h/L (augmented significantly, P < 0.05). The amoxicillin concentrations were slightly elevated by concomitant administration of lansoprazole and clarithromycin but without statistical significance (11.1 versus 12.6 mg/L). For clarithromycin, the time to maximum concentration of drug in serum (Tmax) was increased (2.73 versus 3.31 h, P < 0.05), whereas AUC and Cmax remained unchanged. Simultaneous administration of lansoprazole, amoxicillin and clarithromycin increases the serum concentrations of lansoprazole and the active 14-OH-clarithromycin metabolite significantly. These effects were not so pronounced as to have any therapeutic influence, making dosage adjustment unnecessary.
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Introduction |
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The infection of gastric mucosa by Helicobacter pylori, the causative agent of most chronic active gastritis,1 is an essential cofactor in the aetiology of gastroduodenal ulcer and gastric carcinoma as well as MALT-lymphoma. Peptic ulcer disease and low-malignancy gastric MALT-lymphoma are indisputable indications for therapy.2
The choice of a therapeutic regimen is largely based on empirical trials in humans. An eradication rate of >80% should be achieved.2 Mono and dual therapies yielded unsatisfactory results. Triple therapies with a proton pump inhibitor and two antibiotics had fewer side effects than bismuth, triple or quadruple therapy and were highly effective in the eradication of H. pylori (rates 80–89%).3
Recently, a proton pump inhibitor with clarithromycin and amoxicillin was strongly recommended as a first-line treatment for H. pylori eradication because of the high rate of dual resistance (against metronidazole and clarithromycin) and the limitations of re-treatment regimens after failure of nitroimidazole–macrolide triple therapy.4
A combination of clarithromycin and amoxicillin with lansoprazole (the so-called ‘French’ triple therapy) has proven to be highly effective in the eradication of H. pylori. One week triple therapy with lansoprazole 30 mg, amoxicillin 1000 mg and clarithromycin 250 or 500 mg administered orally twice daily was successful in 89.7–95.2% of patients with duodenal ulcer, gastritis or dyspepsia.5,6
One possible reason for this synergic effect of combination therapy could be the higher bioavailability of the antibiotics in hypoacidity.7,8 Lansoprazole 30 mg once daily had at least the same as or better effect than omeprazole 20 mg once daily in increasing intragastric pH to >5.0.9 Another factor may be the enhanced concentration in gastric secretions and tissue8,10 and of course altered hepatic metabolism by combination of the drugs.
The few studies that investigated pharmacodynamic and pharmacokinetic parameters did not use clinically recommended dosages,8,11–14 and no data are currently available on any mutual pharmacokinetic interaction of the triple combination. In spite of the lack of fundamental knowledge, this kind of triple therapy has been used in gastroenterology for many years. The present study was designed to generate the appropriate data on this issue. The influence of: (i) lansoprazole and amoxicillin on the serum and urine concentrations of clarithromycin and its active metabolite 14-OH-clarithromycin; (ii) lansoprazole and clarithromycin on serum and urine concentrations of amoxicillin; and (iii) amoxicillin and clarithromycin on serum concentrations of lansoprazole was evaluated.
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Materials and methods |
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Subjects
Twelve healthy, H. pylori-negative men were entered into the study after giving their written informed consent. Their mean age, height, weight and creatinine clearance were 27.4 ± 4.32 years, 1.83 ± 0.05 m, 77.6 ± 9.55 kg and 7.0 ± 2.0 L/h/1.73 m2, respectively (means ± S.D.). Exclusion criteria were a regular use of medication within 4 weeks prior to the commencement of the study and during the study, usage of tobacco or alcohol, symptoms of a clinically significant illness within 3 months before the study. A physical examination and a determination of common laboratory parameters for haematological, hepatic and renal functions were performed before, during and after the study. The results were within the normal limits. All participants were H. pylori-negative as determined by a urea breath test (13C-UBT; INFAI GmbH, Bochum, Germany). The study was approved by the Ethical Committee of the Klinikum Benjamin Franklin, Freie Universität Berlin, Germany.
Dosing
The study was randomized, double-blind and had a placebo-controlled four-way crossover design, so that at the end of the study each volunteer had taken each combination of drugs once. The four different regimens consisted of: (i) lansoprazole plus amoxicillin placebo and clarithromycin placebo; (ii) amoxicillin plus clarithromycin placebo and lansoprazole placebo; (iii) clarithromycin plus amoxicillin placebo and lansoprazole placebo; and (iv) lansoprazole plus amoxicillin plus clarithromycin. The single dosages of the study medication were as follows: lansoprazole 30 mg, amoxicillin 1000 mg, clarithromycin 500 mg. Drugs and placebos were taken twice daily for 4 days and once in the morning of day 5 (day of examination). Lansoprazole capsules or lansoprazole placebo had to be taken before breakfast (between 7.00 and 8.00 a.m.) and 12 h later. The antibiotics and their placebos had to be taken 30 min later, also before the meal. On the day of examination the subjects fasted for 12 h before drug adminis- tration. The drugs were swallowed with 100 mL of water; a standard breakfast was served 2 h after the administration of the antibiotics. No caffeinated beverages, alcohol, tobacco, chocolate or citrus fruits were permitted during the study. The study periods were separated by wash-out intervals of 9 days each.
Lansoprazole and amoxicillin as well as their placebo drugs were provided by Grünenthal GmbH, Stolberg, Germany. Clarithromycin and clarithromycin placebo were provided by Abbott GmbH, Wiesbaden, Germany. Packing and labelling were carried out by the head of the clinic pharmacy, Klinikum Benjamin Franklin, Berlin-Steglitz.
Sampling
Blood samples for serum profiles of lansoprazole, amoxicillin, clarithromycin and the 14-OH-clarithromycin metabolite were obtained before dosing of lansoprazole or placebo (0 h) and 0.5, 1, 1.5, 2, 2.5, 3, 4, 8 and 12 h after the intake of the proton pump inhibitor. The sample at 0.5 h was just prior to the administration of the antibiotics or placebos, respectively. The tubes were centrifuged within 30 min of venesection, the serum separated and immediately stored frozen at –80°C.
The first urine samples were provided before medication with lansoprazole (0 h), and thereafter at 0–4, 4–8 and 8–12 h, for the determination of amoxicillin, clarithromycin and 14-OH-clarithromycin metabolite levels. Lansoprazole was not measured in urine.
High-pressure liquid chromatography (HPLC)
Lansoprazole was measured by an HPLC procedure based on a liquid–liquid extraction, enrichment of the analyte and subsequent reversed-phase chromatography using UV-absorbance detection as previously described by Borner et al.,15 an adaptation of two earlier methods.16,17 The lower limit of quantification in serum was 0.042 mg/L, the day-to-day coefficients of variation (CVs) (precision between series) were 16.2–3.1% (concentration range 0.02–2.0 mg/L), and the relative recovery was 98–104%.
Clarithromycin and its 14-OH-metabolite in serum and urine were determined according to the method published by Borner et al.,18 also based on liquid–liquid extraction and reversed-phase chromatography, but with electrochemical detection. For clarithromycin the validation data were as follows: lower limit of quantification in serum 0.5 mg/L, in urine 9.5 mg/L, precision between series 2.2–4.1% for serum and 4.0–4.8% for urine, relative recovery in serum 96.2% and in urine 98–102%. For 14-OH-clarithromycin the lower limit of quantification was 0.56 mg/L in serum and 15.1 mg/L in urine, the CVs from day-to-day were 5.8% for serum and 4.4–5.9% for urine, the relative recovery in serum 94.6% and in urine 104%.
Amoxicillin was extracted from serum by addition of acetonitrile. The protein-free extract was further diluted with mobile phase and chromatographed on a cation exchange column (Nucleosil 5SA, length 250 mm, diameter 4 mm; Macherey & Nagel, Düren, Germany). The mobile phase consisted of 67.5% acetonitrile (v/v), 10% distilled water and 22.5% 0.1 M sodium phosphate buffer, pH 2.92. The apparent pH of the mixture was 4.0 and the sodium concentration was 27 mmol/L. The guard column consisted of Perisorb RP18, length 30 mm, diameter 4 mm (E. Merck, Darmstadt, Germany). The absorbance of the eluate was monitored at 270 nm. The retention time was 6.3 min and the run time was 13 min. Urine was diluted with mobile phase. Validation of the method yielded the following results with serum (urine data in parentheses): detection limit 0.15 mg/L (1.6 mg/L), limit of quantification 0.5 mg/L (15.6 mg/L), linear range 8.0 mg/L (1500 mg/L), precision between series (CVs) 2.3–11.2% (1.8–19.9%), recovery 100.8% (85–104%). Specificity was confirmed by degradation of the amoxicillin peak with ß-lactamase.
Pharmacokinetic analysis
The peak concentration (Cmax), time of peak concentration (Tmax) and terminal half-life (t1/2) were evaluated according to an open one-compartment model for oral application, which was proven to be sufficient by the Schwarz criterion.19 All other parameters were analysed non-compartmentally [area under the concentration–time curve (AUC), clearance (CL) and mean residence time (MRT)].20 Clearance results were adjusted to a body surface of 1.73 m2,21 dose-dependent parameters AUC and Cmax to a mean body weight of 70 kg.22 The calculations were performed by standard methods.20 The regression lines in the figures were determined by a non-linear fitting procedure using the mean concentrations. However, the lines were only used for graphical purposes. The values in the tables are calculated from the individual concentrations. The computer programs used were Microsoft Excel and REVOL as described by Koeppe & Hamann.23
Statistical analysis
Mean estimates and 95% confidence intervals for the determined parameters were analysed and the differences compared by paired t-test. A P value of <0.05 was considered significant.24 Additionally, the test for bio-equivalence was performed for the mean and 90% confidence interval of the log-values of the AUC and Cmax. A result above the expected value (>1.0) indicates a change in the respective parameter.25
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Results |
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All 12 volunteers completed the four periods of the study without any protocol deviation. Regular drug intake was documented in all cases throughout the trial. No adverse events occurred during the treatment with lansoprazole alone. A bitter or metallic taste was noticed by eight volunteers under combination therapy (four), amoxicillin (one) or clarithromycin (three) alone, gastrointestinal symptoms such as soft stools (two), diarrhoea (one) and a slight pressure in the epigastrium (one) were mostly documented under combination therapy (three volunteers) and once under therapy with clarithromycin alone, all mild to moderate in severity. No serious adverse or clinically relevant deviations of laboratory parameters from the reference ranges were reported, hence, the data sets for the pharmacological evaluation included all 12 volunteers enrolled into the study according to their allocation to the treatment order groups.
For each of the three compounds lansoprazole, amoxicillin and clarithromycin, and the 14-OH-clarithromycin metabolite, pharmacokinetic interactions were investigated by comparing serum concentrations of the respective single treatment cycle with serum concentrations obtained under the combination treatment. Urine concentrations of amoxicillin, clarithromycin and 14-OH-clarithromycin both of the single treatment and the combination treatment period were determined. A summary of the pharmacokinetic parameters for each of the study drugs and the active 14-OH-clarithromycin metabolite alone as well as under combination treatment is presented in Table 1, the results for bio-equivalence in Table 2.
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Under combination treatment the AUC0–8 (mg·h/L), t1/2 (h), MRT (h) and the CLtot/f of lansoprazole were increased significantly compared with the single treatment period. Serum concentration–time profiles for lansoprazole are presented in Figure 1a.
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For clarithromycin and 14-OH-clarithromycin a delayed onset of the maximum concentration was measured, Tmax for clarithromycin was 2.73 ± 0.61 h under single treatment compared with 3.31 ± 0.51 h under combination treatment with lansoprazole and amoxicillin (P < 0.05) (Table 1 and Figure 1b). The difference in Tmax for 14-OH-clarithromycin was not significant (P = 0.051), but the AUC0–12 was significantly larger (8.3 ± 2.02 versus 10.5 ± 3.07 mg·h/L, alone versus combination) and the Cmax was significantly higher (0.95 ± 0.19 versus 1.18 ± 0.33 mg/L, alone versus combination) (Tables 1 and 2; Figure 1c).
Smaller urine concentrations after 4 h were observed after combination treatment both for the active substance and its metabolite (Figure 2).
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The total urinary recovery (UR) of 14-OH-clarithromycin referred to the dose of clarithromycin was significantly higher under combination treatment than under single treatment with clarithromycin (30.2 ± 4.0% versus 22.7 ± 10.6%, UR0–12 23.1 ± 3.8% versus 15.6 ± 3.0%, mean ± S.D.); the 12 h total clearance values were not significantly different (Table 1).
No remarkable pharmacokinetic interactions were observed for amoxicillin. Mean values of the serum concentrations were slightly elevated under combination therapy, but these changes were far from being significant (Tables 1 and 2; Figure 1d).
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Discussion |
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The pharmacokinetics of amoxicillin were not altered by simultaneous administration of lansoprazole and clarithromycin. These results are consistent with the data published by other investigators who studied omeprazole and amoxicillin placebo-controlled in different dosages,13,14 and also with the data of Goddard et al.11 giving amoxicillin intravenously at a lower dose. A higher activity of amoxicillin with lower MICs against H. pylori at neutral pH were thought to be the reason for the increased efficacy.7 In rats, oral co-administration of lansoprazole and [14C]amoxicillin led to a significantly higher level of radioactivity in glandular stomach, dependent on the pH.10 Together, these data confirm that the improved antimicrobial effect of dual therapy in eradicating H. pylori is not the result of higher serum concentrations.
Earlier studies investigating the pharmacokinetics of clarithromycin and the active 14-OH-clarithromycin metabolite found comparable values, similar to ours, in the present study.8,11,12,26–28 Our data on clarithromycin serum profiles do not correlate with the augmented concentrations for clarithromycin in plasma when administered with omeprazole found by Gustavson et al.8 The AUCs for omeprazole and clarithromycin were significantly higher, whereas Tmax was not. The dosage was omeprazole 40 mg once in the morning and clarithromycin 500 mg every 8 h for 5 days with a single dose on day 6.8 The increased Tmax of the clarithromycin serum concentration under combination treatment in our data could be because of a delayed absorption due to inhibited gastric secretion as shown before for the combination treatment of clarithromycin and other macrolides with H2-blockers and antacids.29–31
The significantly augmented AUC0–12 and Cmax for 14-OH-clarithromycin as well as the delayed Tmax (3.21 ± 0.47 versus 2.83 ± 0.37 h, P = 0.051) under simultaneous administration of the three drugs support this consideration. The fact that the urine concentrations observed for clarithromycin and its active metabolite after combination treatment were lower in the first 4 h apparently indicates again a delayed absorption of clarithromycin induced by the combination treatment with lansoprazole and amoxicillin.
Cyp3A4 is known to be the main liver enzyme responsible for hydroxylation of clarithromycin. Frequent and rare drug interactions with various substances, including antacids and cimetidine, have been observed.32 An inhibitory effect of lansoprazole on the metabolism of clarithromycin due to a competition at the Cyp3A4 isoenzyme in the liver is not considered to be responsible because of the higher 14-OH-clarithromycin concentration in serum and urine after combination.
The serum concentrations of lansoprazole measured in the study presented here correlated well with the results of other investigators, using equivalent doses.33
In vitro and in vivo studies suggested Cyp2C19 and Cyp3A4 to be responsible for the metabolism of lansoprazole with possible inhibition and induction,34–35 whereas induction of Cyp 1A2 seems to be clinically irrelevant.36
Two volunteers had extremely high serum concentrations, longer half-lives and a reduced clearance for lansoprazole. It is most likely that both volunteers are so-called poor or slow metabolizers. Since we did no Cyp 450-typing this is not proven. The pharmacokinetic profiles of both volunteers following combination therapy were altered in the same way as determined for the others, so that the paired t-test showed a real increase in the AUC and t1/2 in spite of a high standard deviation. The two supposed poor metabolizers showed no alterations in serum concentrations of clarithromycin and 14-OH-clarithromycin compared with the other volunteers, confirming the data of Katsuki et al.37 that the genetic polymorphism with the gene mutation leading to slow metabolization of lansoprazole is related to Cyp2C19 without influencing the Cyp3A4.
Whether the significant changes in AUC, t1/2 and CL for lansoprazole following combination treatment as reported above might be due to metabolic interaction with clarithromycin on the CYP3A level is unclear, since we did not measure Cyp P450 activity. The delayed Tmax together with a higher AUC and Cmax in serum and augmented urine concentrations of 14-OH-clarithromycin makes a prolonged absorption more likely than alterations in metabolization.
In summary, our investigations demonstrated a significant increase of lansoprazole and 14-OH-clarithromycin serum concentrations following simultaneous administration of lansoprazole, amoxicillin and clarithromycin (French triple therapy). However, these effects were not so pronounced as to have any therapeutic influence, making dosage adjustments unnecessary.
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Acknowledgements |
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The technical assistance of J. Vöckler and M. Rau is gratefully acknowledged. This study was supported by Takeda Pharma, Aachen, Germany.
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Footnotes |
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* Correspondence address. Department of Pulmonary and Infectious Diseases, City Hospital Berlin-Heckeshorn, affil. Freie Universität Berlin, Zum Heckeshorn 33, 14109 Berlin, Germany. Tel: +49-30-8002-2222; Fax: +49-30-8002-2623; E-mail: haloheck{at}zedat.fu-berlin.de
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