Volume 44, No. 7/2006(July)
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 Int. Journal of Clinical Pharmacology and Therapeutics
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Pharmacogenetics Review
Clinical impact of CYP2C19 polymorphism on the action of proton pump inhibitors: a review of a special problem
Abstract
U. Klotz
Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany
Proton pump inhibitors (e.g. omeprazole/esomeprazole, lansoprazole, pantoprazole, rabeprazole) have a prominent role in the short- and long-term management of acid-related intestinal disease. They are eliminated by the hepatic route and the polymorphic CYP2C19 is involved in their metabolism. Three phenotypes have been identified in various populations: extensive metabolizers (homEM), poor metabolizers (PM) and individuals carrying one wild type and one mutant allele (hetEM). Therefore, systemic drug exposure (AUC) varies widely between these three populations and the AUC for omeprazole, lansoprazole and rabeprazole are approximately 7.5-, 4.5- and 4-fold higher in PM than in homEM. Since the pharmacodynamic response to proton pump inhibitors (PPIs) is related to their AUC, intragastric pH is much more elevated in PM (median around 6) and hetEM (4 – 5) than in homEM (3 – 4). This genotype-dependent increase in AUC and intragastric pH has clinical consequences because the healing rate in peptic ulcer (PU, target pH ³ 3) and gastroesophageal reflux disease (GERD, target pH ³ 4) and the eradication of Helicobacter pylori (Hp) depend on a long-lasting (³ 16 hours) and effective inhibition of acid secretion. Several clinical studies have shown that PM and hetEM benefit from an approximately 18% higher Hp eradication rate compared to homEM when standard dosages of PPIs are administered orally. In our own study with lansoprazole (+ amoxicillin, clarithromycin, metronidazole) the eradication rates were 100, 98 and 80% in PM, hetEM and homEM, respectively, and in patients with GERD treated with lansoprazole (30 mg/day) the healing rates after 8 weeks were much higher in PM (85 – 100%) and hetEM (68 – 95%) than in homEM (46 – 77%). In a further study with esomeprazole (40 mg/day) in 205 patients with GERD we were surprised to observe that the healing rate after 4 weeks was not dependent on the CYP2C19 genotype. In an accompanying pharmacokinetic trial in 10 patients with GERD, both esomeprazole and 5-OH-esomeprazole (formed by CYP2C19) plasma levels and those of omeprazole-sulfone (formed by CYP3A4) were determined. Based on the calculated metabolic ratios it could be shown that CYP3A4 plays a major role in kinetics of esomeprozale, particularly after multiple dosing when there is a metabolic shift in favor of the formation of the sulfone.
In conclusion, for most PPIs the activity of CYP2C19 determines the level of drug exposure (AUC), pharmacodynamic response (elevation of intragastric pH and serum levels of gastrin) and clinical outcome (Hp eradication, healing rates of PU and GERD). Thus, a genotype-adjusted dosage regimen will improve therapeutic efficacy of PPIs.Correspondence to:
Prof. Dr. U. Klotz
Dr. Margarete Fischer-Bosch-Institut für Klinische Pharmakologie
Auerbachstraße 112
70376 Stuttgart, Germany
Email: ulrich.klotz@ikp-stuttgart.de
Pharmacokinetics
Maturational changes in the in vivo activity of CYP3A4 in the first months of life
Abstract
K. Allegaert1,2, J.N. Van den Anker3,4,5, A. Debeer1, V. Cossey1, R. Verbesselt6, D. Tibboel2, H. Devlieger1 and J. de Hoon6
1Neonatal Intensive Care Unit, University Hospital, Gasthuisberg, Leuven, Belgium, Departments of 2Pediatric Surgery and 3Pediatrics, Erasmus Medical Center, Sophia’s Children Hospital, Rotterdam, The Netherlands, 4Division of Pediatric Clinical Pharmacology, Children’s National Medical Center, 5Departments of Pediatrics, Pharmacology and Physiology, The George Washington University School of Medicine and Health Sciences, Washington, DC, USA, 6Center for Clinical Pharmacology, University Hospital, Gasthuisberg, Leuven, Belgium
Objective: To document maturational changes of the in vivo activity of CYP3A4 in the first months of life. Methods: The contribution of tramadol (M), O-demethyl tramadol (M1, CYP2D6-mediated) and N-demethyl tramadol (M2, CYP3A4-mediated) to the overall elimination of tramadol and the log M/M2 was assessed in 24-hour urine collections during continuous intravenous tramadol administration. Correlations with perinatal characteristics (postnatal age (PNA) and postmenstrual age (PMA)) were studied. Results: Of the total amount of tramadol administered in a 24-hour interval to 25 neonates and young infants (PMA 25 – 53 weeks), 34.5% (SD 6.1) were retrieved in the urine as parent compound or metabolite in a 24-hour interval. This retrieved material consisted primarily of tramadol 79% (SD 18), M1 10% (SD 17) and M2 3% (SD 3.4). The contribution of M (r2 = –0.53), M1 (r2 = 0.46) and M2 (r2 = 0.16) to overall M elimination correlated with increasing PMA. The mean log M/M2 was 1.44 (SD 0.46) and there was an inverse correlation between the log M/M2 ratio and PMA (r2 = –0.43, 95% CI for r = –0.84 to –0.34, p = 0.0006) and PNA (r2 = –0.25, 95% CI for r = –0.78 to –0.16, p = 0.008). The maturational half-life of the log M/M2 ratio was 16 – 20 weeks. In a multiple regression model, PMA was the only significant variable accounting for the interindividual variability in log M/M2. Conclusions: PMA was found to be the most important maturational change determing the in vivo activity of CYP3A4. The activity of CYP3A4 is relatively delayed in the first months of life compared to the developmental changes in CYP2D6 activity described earlier, however, the overall weak correlations reflect that PMA explains only in part the interindividual variability observed.Correspondence to:
K. Allegaert, MD, PhD
Neonatal Intensive Care Unit
Division Woman and Child
University Hospital
Gasthuisberg
Herestraat 49
3000 Leuven, Belgium
Email: karel.allegaert@uz.kuleuven.ac.be
Therapeutics
Glucocorticoid treatment in patients with septic shock: effects on vasopressor use and mortality
Abstract
A. Boyer, K. Chadda, A. Salah and D. Annane
1Critical Care Department, CHU Bordeaux, Bordeaux, Cedex, France, 2Intensive Care Unit, Homerton University Hospital, London, Great Britain, and 3Critical Care Department, Université de Versailles Saint-Quentin en Yvelines, Assistance Publique – Hôpitaux de Paris, Hôpital Raymond Poincaré, Garches, France
Corticosteroids were proposed for the treatment of sepsis as early as 1940. Several RCTs cast serious doubts on the usefulness of high dose corticosteroids and doubt still persists regarding the efficacy of replacement therapy. Adrenal insufficiency (non-responders to the 250 mg corticotropin test: increase in cortisol < 9 mg/dl) is present in about half of patients with septic shock and is associated with higher rates of refractory hypotension and mortality. Peripheral glucocorticoid resistance, which may even occur more frequently, can be easily assessed at bedside using skin tests. Cortisol antagonizes the migration of inflammatory cells, the synthesis or action of virtually all proinflammatory mediators, promotes virtually all anti-inflammatory components and enhances humoral immunity by means of transcriptional interference between its receptor and both AP-1 and NF-kB. Cortisol mediates cardiovascular tolerance to endotoxin and the maintenance of vascular sensitivity to catecholamines. Low doses (about 300 mg daily for 5 days or more) of hydrocortisone increase vasoconstrictor response to catecholamines in animals, in healthy volunteers challenged with LPS and in several RCTs. Hydrocortisone also increases arterial pressure and decreases the duration of shock. A meta-analysis of all available clinical controlled studies showed a reduction in 28 days, all-cause mortality with glucocorticoids (RR = 0.88, 95% CI: 0.78 – 1.00; p = 0.04). However, there was a significant heterogeneity across the trials (p = 0.006). On the other hand, analysis of studies where low doses of glucocorticoids were given for prolonged periods showed a 24% reduction in the risk of all-cause mortality at 28 days in treated patients (RR = 0.76, 95% CI: 0.64 – 0.90; p = 0.002) without heterogeneity across the trials (p = 0.28). In conclusion, in severe sepsis, high doses of corticosteroids should not be given. Septic shock should be treated with a replacement dose of hydrocortisone. Correspondence to:
D. Annane, MD, PhD
Professor of Intensive Care Medicine
Head of Critical Care Department
Université de Versailles Saint-Quentin en Yvelines
Assistance Publique – Hôpitaux de Paris
Hôpital Raymond Poincaré
92380 Garches, France
Email: djillali.annane@rpc.ap-hop-paris.fr
Therapeutics
Dipyridamole/aspirin combination in secondary stroke prevention: effects on absolute myocardial blood flow and coronary vascular resistance
Abstract
W.M. Schaefer1, K.-C. Koch2, B. Nowak1, J. Noth3, U. Buell1 and P.H. Weiss3
Departments of 1Nuclear Medicine, 2Cardiology, Medical Clinic I, 3Department of Neurology, University Hospital Aachen, Germany
Objective: In the European Stroke Prevention Study (ESPS 2), oral administration of a fixed combination of 200 mg extended-release dipyridamole and 25 mg aspirin (twice daily) after ischemic stroke or transient ischemic attack, significantly reduced the risk of stroke compared to placebo as well as compared to aspirin or dipyridamole alone. However, the i.v. application of dipyridamole over 4 – 6 min is known to increase myocardial blood flow up to 6-fold, and thereby potentially provoke ischemic wall motion abnormalities in patients with coronary artery disease. We therefore assessed the cardiac side effects of the dipyridamole/aspirin combination on absolute myocardial blood flow (MBF) and coronary vascular resistance (CVR). Methods: MBF and CVR were measured using 15O-water positron emission tomography in 24 patients after stroke or transient ischemic attack, before and 6.7 ± 1.9 days after starting the dipyridamole/aspirin combination (Aggrenox) therapy. Results: Resting MBF increased by 39% (max. 112%), from 0.92 ± 0.13 (ml × g–1 × min–1) at baseline to 1.28 ± 0.27 (ml × g–1 × min–1) under ongoing dipyridamole/aspirin combination therapy (p < 0.0005). CVR consecutively decreased from 105.3 ± 16.9 to 74.1 ± 16.5 (mmHg × ml–1 × g × min) (p < 0.0005). The relative increase in MBF correlated negatively with the body surface area. No correlation was found between relative MBF increase and duration of dipyridamole/aspirin combination therapy (range 4 – 10 days). Conclusions: Orally administered dipyridamole/aspirin combination therapy in secondary stroke prevention increases MBF and decreases CVR significantly. These cardiac side effects of the dipyridamole/aspirin combination should be taken into account in stroke patients with proven or suspected coronary artery disease, particularly in combination with a small body surface area. Correspondence to:
W. M. Schaefer, MD, PhD
Department of Nuclear Medicine
University Hospital Aachen
Pauwelsstraße 30
52074 Aachen, Germany
Email: wschaefer@ukaachen.de
Drug Interactions
Pharmacokinetic interaction between ketoconazole and SPP301 in healthy volunteers
Abstract
W. Dieterle and J. Mann
1Drug Disposition Consultants, Loerrach, Germany, 2Clinical Research and Development, Speedel Pharma AG, Basle, Switzerland
Background: SPP301 is a potent and highly selective ETA receptor blocker. The primary aim of the present study was to investigate the effect of the potent CYP3A4 inhibitor ketoconazole on the pharmacokinetics of SPP301. Methods: In a randomized, open-label 2-period oral crossover study, 12 healthy male subjects received treatments A and B. Treatment A consisted of 200 mg ketoconazole once daily on Days 1 – 4 and concomitantly 5 mg SPP301 on Day 3. Treatment B consisted of 5 mg SPP301 administered alone. Plasma concentrations of SPP301 and its hydroxymethyl metabolite were measured by LC-MS/MS. Results: Ketoconazole coadministration increased the systemic availability of SPP301 and its hydroxymethyl metabolite 3-fold and prolonged their half-lives by a factor of 2. The ratios of least square means (90% CI) of pharmacokinetic parameters in the presence and absence of ketoconazole for SPP301 and its metabolite were Cmax (maximum plasma concentration) 1.22 (1.13, 1.32) and 1.2 (1.05, 1.37), AUC(0-¥) (area under the plasma concentration-time curve from time zero to infinity) 3.16 (2.84, 3.51) and 3.14 (2.49, 3.70) and t1/2 (apparent terminal half-life) 2.21 (1.55, 2.87) and 2.00 (1.17, 2.84), i.e. an increase of systemic exposure by a factor of 3.2, with individual exposures increasing up to 5.9-fold. Single oral doses of SPP301 were well tolerated when administered alone or together with multiple doses of ketoconazole. Conclusion: In the presence of potent CYP3A4 inhibitors exposure of SPP301 may be increased up to 6-fold.Correspondence to:
Jessica Mann, MD, PhD
Speedel Pharma AG
Department of Clinical Research and Development
Hirschgässlein 11
4051 Basel, Switzerland
Email: jessica.mann@speedel.com
Adverse Drug Reactions
Possible macular exanthema associated with linezolid therapy
Abstract
J. Borrás-Blasco1, J.M. Vicent Verge2, D. Rosique-Robles1, A. Galan-Brotons2, E. Casterá1 and V. Giner-Marco2
1Hospital Pharmacy, Pharmacy Service, and 2Clinical Oncology, Oncology Service, Hospital de Sagunto (Valencia), Spain
Objective: To report a case of macular exanthema associated with linezolid therapy. Case summary: A 54-year-old white man diagnosed as having laryngeal epidermoid carcinoma attended our emergency department because of fatigue, fever, neck pain and a fistulized fixed mass in the right side of the neck with purulent exudation. Treatment with amoxicillin/clavulanic acid 875 mg/125 mg p.o. every 8 hours as empirical therapy was started. Cultures of the exudates from the fistula confirmed the presence of methicillin-resistant Staphylococcus aureus (MRSA). Amoxicillin/clavulanic acid was discontinued and therapy was started with linezolid 600 mg p.o. every 12 hours but 5 days after commencing linezolid the patient came to our emergency room because of generalized erythematous macular eruptions. A diagnosis of severe and generalized macular exanthema induced by linezolid was made. Administration of linezolid was suspended and there was an improvement in the skin lesions and general state of health. The patient was discharged without further symptoms. Discussion: In this case, there was a close temporal correlation between drug exposure and the onset of symptoms. When linezolid was discontinued, the skin lesions resolved quickly and the general condition of the patient improved. Furthermore, linezolid was the only drug added before the cutaneous lesions appeared. It is possible that the adverse reaction was associated with administration of amoxicillin/clavulanic acid. However, the patient had been treated with this antibiotic previously without appearance of any cutaneous reaction. An objective causality assessment revealed that an adverse effect was possible. Conclusion: Based on our observations, we conclude that linezolid was the most likely cause of the adverse reaction. Clinicians should be aware of this infrequent but severe reaction.Correspondence to:
J. Borrás-Blasco
Pharmacy Department
Hospital de Sagunto
Avda Ramon y Cajal s/n
Sagunto 46520 (Valencia), Spain
Email: jborrasb@sefh.es
Drug Utilization
Potentially inappropriate prescribing for insomnia in elderly outpatients in Taiwan
Abstract
W.-F. Huang1 and I.-C. Lai2
1Institute of Health and Welfare Policy, College of Medicine, National Yang Ming University, Taipei, and 2Department of Psychiatry, Yu-Li Veterans Hospital, Hualien, Taiwan
Objective: This study was based on Taiwan’s National Health Insurance (NHI) claim records with the aim of identifying specific types of potentially inappropriate sedative-hypnotic prescribing in elderly outpatients with insomnia. The potentially inappropriate prescribing included duplicate treatment, excessive dosage and duration or treatment and prescribing of hypnotics that are too long-acting. Material and methods: This cross-sectional study was based on annual outpatient claim data for 2001 released by Taiwan’s Bureau of National Health Insurance (BNHI). A subset was created for patients aged 65 years or older and coded as having insomnia. Physician consultation claim data were extracted and merged in 1 claim file consisting of ICD-9-CM codes, patient demographic data, specialty of physicians, medical institution code and pharmaceutical prescription content. Results: Elderly patients with insomnia constituted 216,994 of the 1,000,193 files surveyed on outpatient claims in 2001. The mean age was 74.33 years and gender distribution was nearly equal. Of the prescribed sleep medications, 41.26% were hypnotic benzodiazepines, 29.36% were hypnotic non-benzodiazepines and 29.38% were sedative-anxiolytics. Approximately 1 in 25 patients (4.12%) of all the patients prescribed hypnotics received duplicate treatment, 1 in 8 an inappropriately (12.27%) high dosage (daily dose > 1.5 DDD, Defined Daily Dose), 1 in 3 (32.25%) more than 28 DDD per prescription and 1 in 6 (17.52%) a drug with an effect which was too prolonged. Physicians tended to consider patient gender but not age when prescribing. Clear trends were found between the specialty of the physician and the type of inappropriate prescribing. The type of medical institution was significantly related only to the excessive quantity of medication prescribed. Conclusions: Elderly people in Taiwan with insomnia receive potentially inappropriate prescriptions for sleep medications. Similar data could possibly be extracted from similar databases in other countries throughout the world. Some of these potentially inappropriate prescriptions are avoidable in terms of restricting the length of outpatient sedative-hypnotic treatment, introducing hypnotics in small dosage forms and continuously educating clinicians on the safety of geriatric medication.Correspondence to:
W.-F. Huang, PhD
Associate Professor Institute of Health and Welfare Policy
College of Medicine
National Yang Ming University, No.155
Li-Nong Street Section 2, Taipei, Taiwan 112
Email: huang@ym.edu.tw
