Pharmacodynamic modeling of the acid inhibitory effect of ranitidine in patients in an intensive care unit during prolonged dosing: Characterization of tolerance

Mathôt, Ron A. A.; Geus, W. P.

doi:10.1053/cp.1999.v66.99988

Cited by 30 publications

(3 citation statements)

References 43 publications

(52 reference statements)

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“…Although estimates for the Hill constant in our model are large and argue the potential application of a fixed-effects model to these data sets, this finding is not surprising given the limited data available as input values in our model. In addition, similarly large values for this constant have been reported previously for the pharmacodynamic modeling of ranitidine in adult subjects, despite the availability of a considerably greater number of data points available for analysis (23). Moreover, comparison of these pharmacokinetic and pharmacodynamic estimates with those generated by the respective model-independent approaches were in general agreement, so some degree of validation in using a simple model-dependent approach for characterizing the pharmacokinetic-pharmacodynamic link for nizatidine in this population is afforded.…”

Section: Pharmacodynamicssupporting

confidence: 68%

Developmental Pharmacokinetics and Pharmacodynamics of Nizatidine

Abdel‐Rahman,

Johnson,

Connor

et al. 2004

J. pediatr. gastroenterol. nutr.

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Objectives:To characterize the impact of development on the pharmacokinetics and pharmacodynamics of nizatidine.Methods:Children (age range, 5 days–18 years) and adults (age range, 18–50 years) were enrolled in four open‐label trials. Nizatidine formulation and dose were determined by age: infants received 2 or 4 mg/kg IV, children 2.5 or 5 mg/kg in one of three oral liquid formulations, and adolescents and adults received a fixed 150‐mg capsule. Nizatidine and N‐desmethylnizatidine concentrations were measured in serial post‐dose plasma samples by a high‐performance liquid chromatographic assay with mass spectrometric detection. Intragastric pH was recorded during a 24‐hour post‐dose interval.Results:Data on 93 subjects were combined with previous values from 36 individuals to cover an age group not adequately captured and to control for formulation effects. Dose‐normalized exposure estimates revealed no apparent age dependence; however, maximum plasma concentration (298.5 ± 100.7 v 552.8 ± 152.4 ng/mL per mg/kg dose) and AUC0‐∞ (954.4 ± 379.8 v 1,573.0 ± 347.4 ng*hour/mL per mg/kg dose) were reduced in extemporaneous formulations in apple juice. The apparent modest age dependence observed for total body clearance (Cl/F) (r2 = 0.365) and Vss/F (r2 = 0.221) reflected a formulation‐dependent decrease in bioavailability rather than a true age effect. The age‐associated changes in λz observed for nizatidine and its metabolite were predictable and consistent with developmental acquisition of renal function. Mean and median pH, as well as fraction of time that the dosing interval remained above target pH values, were significantly greater with administration of the drug than without.Conclusions:The biodisposition of nizatidine in children and adults is similar; however, response after a comparable weight‐based dose is equal and potentially greater in children.

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Section: Pharmacodynamicssupporting

confidence: 68%

Developmental Pharmacokinetics and Pharmacodynamics of Nizatidine

Abdel‐Rahman,

Johnson,

Connor

et al. 2004

J. pediatr. gastroenterol. nutr.

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“…[8] The pharmacodynamic study can be confounded by the complexity of mechanisms responsible for the elimination of the active drug/metabolite or competing biological mechanisms via alternate biological pathways as exemplified in the hysteresis seen in the dose/response results of the acid inhibitory effect study of ranitidine. [9] Phase 1 studies establish the dose that is tolerated in humans and consist of single-dose and multiple-dose studies including dose escalation protocols that examine any potential side effects. The starting clinical dose is typically 1% of the no-effect level seen for toxicity in animal studies.…”

Section: Phasementioning

confidence: 99%

Safety and Efficacy: The Role of Chemistry, Manufacturing, and Controls in Pharmaceutical Drug Development

Difeo

2004

Drug Development and Industrial Pharmacy

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“…Tolerance develops with IV administration of H 2 RAs within 42 hours. This occurs in the ICU with repeated and continuous infusion [25,26]. The reduction in the antisecretory effect of H 2 RAs is not explained by altered pharmacokinetics.…”

Section: Routes Of Administrationmentioning

confidence: 99%

Stress-related mucosal disease

Spirt¹

2003

Curr Treat Options Gastro

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Stress-related mucosal disease (SRMD) includes stress-related injury (superficial mucosal damage) and stress ulcers (focal deep mucosal damage). Both types are caused by mucosal ischemia, and both show a propensity for the acid-producing corpus and fundus. Prophylaxis of stress ulcers may reduce major bleeding but, so far, has not been shown to improve survival. The most widely used drugs for stress-related injury are the intravenous histamine H(2)-receptor antagonists. Proton pump inhibitors (PPIs) are the most potent acid-suppressive pharmacologic agents. The available PPIs significantly increase gastric pH for up to 24 hours after one dose. Tolerance does not develop, and adverse effects are few. Preliminary studies have demonstrated a significant reduction in SRMD bleeding for patients receiving PPI prophylaxis. PPIs may become an effective tool for reducing the incidence of SRMD in critically ill patients.

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Pharmacodynamic modeling of the acid inhibitory effect of ranitidine in patients in an intensive care unit during prolonged dosing: Characterization of tolerance

Cited by 30 publications

References 43 publications

Developmental Pharmacokinetics and Pharmacodynamics of Nizatidine

Developmental Pharmacokinetics and Pharmacodynamics of Nizatidine

Safety and Efficacy: The Role of Chemistry, Manufacturing, and Controls in Pharmaceutical Drug Development

Stress-related mucosal disease

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