The pharmacokinetics of single 50 mg oral and intravenous doses of milnacipran, a new non tricyclic antidepressant drug, were compared in 11 chronic liver impaired (LI) subjects and in 6 control subjects. Hepatic impairments, classified according to the PUGH scale were moderate (1 grade A), intermediate (6 grade B) and severe (4 grade C). Concentrations of unchanged drug and its conjugated form (its main metabolite) were measured in plasma and urines. In control subjects, milnacipran present high absolute bioavailability (mean value of 90%). Around 50% of the dose are excreted in urines as unchanged, while around 14% are excreted as glucuroconjugate. The remaining is composed of free and conjugated phase I inactive metabolites. Administration of milnacipran in LI subjects results in non significant changes in its pharmacokinetics, although its variability is increased. Unchanged drug exposure is not modified in LI subjects, while plasma levels of the conjugate are slightly decreased compared to the control group. This could either be due to a slight reduction in the conjugation process, or to a change in the distribution of the drug as urine excretion of both unchanged and conjugated forms are not modified compared to the control group. A few LI subjects present supra-bioavailability resulting in higher drug exposure after oral administration than after intravenous infusion. These modifications are not clinically relevant as drug exposure of the parent drug is not modified. As the unchanged drug is the only compound responsible for the activity of milnacipran, no dosage adjustment is needed in patients presenting liver impairment.

The pharmacokinetics of a single 50 mg dose of milnacipran, a new non tricyclic antidepressant drug, were compared in 8 chronic renal failure subjects (Clc(reat) between 9 to 84.5 ml.min(-1)) and in 6 healthy volunteers. Concentrations of unchanged (F2207 racemate and F2695 and F2696, enantiomers) and glucuroconjugated drug (main metabolite) were measured using HPLC and GC-MS. As for drugs mainly eliminated via renal route, the pharmacokinetics of milnacipran were markedly affected by impaired renal function with the elimination half-life of severely impaired subject being approximately three times that of the control group. Milnacipran apparent total clearance and renal clearance were positively correlated with glomerular filtration rate, while non-renal clearance and apparent volume of distribution were unaffected by renal impairment. Plasma concentrations of the glucuroconjugate were gradually increased in plasma, while its total urine excretion remained unchanged. As for the racemate, pharmacokinetics of each enantiomer were modified by renal failure, although, as predictable from its higher renal clearance value, it was more marked for F2696 than for F2695. Considering that modifications were shown to be proportional to the degree of renal impairment and that milnacipran presents low variability, the necessary dose adjustment is therefore easy to predict.

The pharmacokinetics of ciprofloxacin has been studied after a single oral dose of 500 mg given to 5 normal subjects (N) and to 15 patients grouped according to their residual renal creatinine clearance: Group I, 8-30 ml X min-1, Group II, less than 8 ml X min-1, and Group III, haemodialysed patients studied twice--during an interdialysis period (IIIa) and in a 4 h haemodialysis session (IIIb). Ciprofloxacin was assayed by reverse phase HPLC using a spectrofluorimetric detection. The peak plasma concentration (2-5 mg X l-1) was reached within 2 h after drug administration. Apparent volume of distribution, 6.6 (N), 5.0 (I), 2.7 (II) and 4.2 (IIIa) l X kg-1 and total plasma clearance, 770 (N), 440 (I), 378 (II) and 314 (IIIa) ml X min-1 were decreased in relation to the degree of renal impairment. Mean plasma half-lives for patients in the 4 groups were 7.3 (N), 10.4 (I), 7.2 (II) and 9.3 (IIIa) h. In groups N, I and II, 40, 16 and 8% of the administered dose was eliminated through the kidney, with mean renal clearances of 305 +/- 63, 61 +/- 21 and 21 +/- 3 ml X min-1. A linear relationship was found between the renal clearance of ciprofloxacin and the glomerular filtration rate (r = 0.75, n = 15). Ciprofloxacin was partly removed by haemodialysis (IIIb): the dialyser extraction ratio was 23% and the dialysis clearance was 40 ml X min-1.

Several standardized assessment procedures are currently used in the evaluation of adverse drug reactions (ADRs). Disagreement in rating ADRs can result from between-raters variability and between-methods differences in weighting the evidence. We eliminated between-raters variability by computer simulation of 1134 ADRs (including all the possible combinations of criteria currently used) and by automatic rating using different algorithms adapted from six published methods. Percentage agreement (Po) and weighted kappa test (kappa w) between pairs of methods are always better than with randomized scores, but the strength of agreement is only moderate (0.26 less than Po less than 0.59; 0.14 less than kappa w less than 0.51). The weightings of criteria are evaluated in terms of sensitivity, specificity, and predictive values. Criteria are neither sensitive (0.41 less than Se less than 0.70) nor specific (0.18 less than Sp less than 0.63) and have poor predictive values. Disagreements on weightings are considerable for three major criteria: timing of event, dechallenge, and alternative etiologic candidates. We discuss some ways of improving reliability of ADR diagnosis.

We investigated the kinetics of cefotaxime in eight subjects undergoing continuous ambulatory peritoneal dialysis (CAPD). A single 1 gm iv dose was injected and a 1 gm dose was given intraperitoneally in the CAPD fluid during a 4-hour dwell time. Cefotaxime and desacetylcefotaxime were assayed by HPLC. After intravenous injection the cefotaxime serum kinetic parameters were as follows: plasma t 1/2, 2.31 +/- 0.20 hours; volume of distribution, 0.35 +/- 0.04 L/kg; total plasma clearance, 118.7 +/- 12.3 ml/min; and peritoneal clearance, 6.7 +/- 1.3 ml/min. Dialysate cefotaxime concentrations rose rapidly, but only 5% of the dose was eliminated by the peritoneal route. After intraperitoneal instillation, cefotaxime appeared in the serum rapidly and the peak serum concentrations ranged from 9 to 20 micrograms/ml between 1 and 3 hours. The absorption of cefotaxime from peritoneal space was 58.7% +/- 5.4%. Data suggest that cefotaxime has bidirectional exchange characteristics through the peritoneal membrane. Instillation of cefotaxime in CAPD fluid may permit rapid absorption to achieve therapeutic serum concentrations.