J Clin Pharmacol

Pharmacokinetics of metoclopramide in neonates.

Year 1998
Kearns GL. van den Anker JN. Reed MD. Blumer JL.
Department of Pediatrics, University of Missouri-Kansas City, MO 64108, USA.
Despite its wide use as a prokinetic agent in neonates and infants with gastroesophageal reflux (GER), the pharmacokinetics of metoclopramide have not been characterized in this pediatric subpopulation. A single-dose pharmacokinetic study of oral metoclopramide (0.1 to 0.15 mg/kg) was performed in 10 fasted premature infants (weight 1.1 to 3.2 kg) ranging from 31 to 40 weeks postconceptional age. Metoclopramide was quantitated from repeated blood samples (n = 9 over 24 hours) by high-performance liquid chromatography. A one-compartment open model with first-order absorption best described the plasma concentration-time data. No correlations were observed between gestational, postnatal, or postconceptional age and any of the pharmacokinetic parameters studied. Comparison of the pharmacokinetic parameters from the study cohort and those reported previously from a similar study of older infants revealed no statistically significant differences. However, a prolonged apparent plasma clearance (Cl/F) of metoclopramide was observed in 30% of the infants studied, and the mean Cl/F and apparent steady-state volume of distribution (Vdss/F) were approximately 1.4- and 2.1-fold higher, respectively, than values reported in previous studies of metoclopramide disposition in adults. These data suggest that metoclopramide pharmacokinetics may exhibit a developmental dependency. Thus, a metoclopramide dose of 0.15 mg/kg given orally every 6 hours is recommended for the initiation of prokinetic therapy with this agent in infants who are < or = 31 weeks postconceptional age.

Clinical endoscopic evaluation of the gastroduodenal tolerance to (R)- ketoprofen, (R)- flurbiprofen, racemic ketoprofen, and paracetamol: a randomized, single-blind, placebo-controlled trial.

Year 1998
Jerussi TP. Caubet JF. McCray JE. Handley DA.
Sepracor, Inc., Marlborough, MA 01752, USA.
Ketoprofen, a nonsteroidal anti-inflammatory drug (NSAID) of the 2-arylpropionic acid class, causes gastroduodenal hemorrhages and erosions in 10-15% of patients. The (S)- enantiomer exhibits most of the anti-inflammatory properties, with concomitant gastrointestinal toxicity. The (R)- enantiomer, however, was recently found to have analgesic properties independent of prostaglandin inhibition. Seventy-two healthy male volunteers not receiving NSAIDs, alcohol, or anti-ulcer drugs, were enrolled in a randomized, investigator-blind, placebo-controlled trial to evaluate the gastroduodenal tolerance of (R)- ketoprofen 100 mg b.i.d., (R)- flurbiprofen 100 mg b.i.d., racemic ketoprofen 100 mg b.i.d., and paracetamol 1,000 mg b.i.d. Gastroduodenal endoscopies at baseline and after 2.5 days of dosing were used to detect newly occurring hemorrhages and erosions. Adverse events were also recorded. The incidence of submucosal hemorrhages was 4/16 in the (R)- ketoprofen group, 5/16 in the (R)- flurbiprofen group, 12/16 in the racemic ketoprofen group, 1/16 in the paracetamol group, and 1/8 in the placebo group. The incidence of erosions was 2/16 in the (R)- ketoprofen group, 4/16 in the (R)- flurbiprofen group, 10/16 in the racemic ketoprofen group, 0/16 in the paracetamol group, and 2/8 in the placebo group. The differences in hemorrhages and erosions among treatments were statistically significant (gastric hemorrhages P = 0.0008; duodenal hemorrhages P = 0.00062; gastric erosions P = 0.0004; duodenal erosions P = 0.0062, Kruskal-Wallis test). At 100 mg b.i.d., (R)- ketoprofen caused fewer gastroduodenal hemorrhages and erosions than racemic ketoprofen (P = 0.019, P = 0.0112, P = 0.0097, P = 0.0139 for gastric, duodenal hemorrhages and gastric, duodenal erosions, respectively). The difference between 100 mg b.i.d. (R)- ketoprofen and 100 mg b.i.d. (R)- flurbiprofen was not statistically significant. The dissociation between analgesic and anti-inflammatory properties for (R)- ketoprofen suggests that it may represent a unique analgesic with a favorable safety profile.

Pharmacokinetics and pharmacodynamics of irbesartan in patients with hepatic cirrhosis.

Year 1998
Marino MR. Langenbacher KM. Raymond RH. Ford NF. Lasseter KC.
Department of Clinical Pharmacology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000, USA.
The effect of hepatic impairment on the clinical pharmacology of the angiotensin II (AII) receptor antagonist irbesartan was assessed by comparing pharmacokinetic and pharmacodynamic parameters in 10 patients with hepatic cirrhosis with a matched group of 10 healthy volunteers. The pharmacokinetics and pharmacodynamics of irbesartan, 300 mg taken orally once daily, were evaluated after single- and multiple-dose (7 consecutive days) administration to normotensive subjects in an open-label, multiple-dose, parallel group study. Pharmacokinetic data obtained after administration of single and multiple doses of irbesartan showed no significant difference between the two groups in time to maximum observed plasma concentration of drug (tmax), half-life (t1/2), area under the plasma concentration-time curve (AUC), apparent oral clearance (Cl(t)/F), renal clearance (Cl(r)), and accumulation index (AI). Steady-state levels of irbesartan were reached within 3 days in both treatment groups. After irbesartan administration on day 1, mean increases from baseline in plasma AII levels and plasma renin activity (PRA) were greater in the group with cirrhosis than in the control group. On day 7, mean increases from baseline in PRA were greater in the control group than in the group with cirrhosis. No discontinuations or serious adverse events occurred during the study. The pharmacokinetics of irbesartan after repeated oral administration were not significantly affected in patients with mild-to-moderate cirrhosis of the liver. No dosage adjustment is necessary in patients with hepatic insufficiency.