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Notes: Abstract Severe malnutrition has been associated with a decrease in fat and lean body mass, as well as in renal function. This study was designed to evaluate the estimation of glomerular filtration rate (GFR, ml/min per 1.73 m2) in malnourished teenagers, by using the formula GFR=kL/P cr (whereL is body height,P cr is plasma creatinine concentration and k is a proportionality constant relating muscle mass to body size that has been found to equal 0.7 in adolescent boys and 0.55 in girls). Body composition was estimated using anthropometric measurements and urinary creatinine excretion (UcrV). Malnourished female patients showed depletion of fat and muscle, whereas males had primarily decreased muscle mass. There was a good correlation (r=0.74) between anthropometric [arm muscle volume (AMV)] and chemical UcrV estimates of muscle mass. However, our previously validated estimate of GFR did not give reliable results in this group of malnourished teenagers, probably because their muscle mass was so greatly altered by the severity of malnutrition. Therefore, we used anthropometric measurements and Pcr, to estimate GFR by multiple linear regression. The best prediction was obtained by using AMV/Pcr and the observed/expected (for age, height and sex) weight ratio (WR): $$\begin{gathered} GFR (ml/min) = 0.06 AMV/P_{{\text{cr}}} + 131{\text{ WR - 79,}} \hfill \\ r = 0.82,n = 13. \hfill \\ \end{gathered} $$ We confirm that malnutrition in adolescents is associated with decreased GFR and conclude that the resulting variability in body composition limits the possibility of estimating GFR from Pcr and height. A somewhat better estimate may be obtained from simple anthropometric measurements and Pcr.

Notes: Abstract Background:This study was performed to evaluate thepharmacokinetics, bioequivalence, and feasibility of a combined oralformulation of 5-flurouracil (5-FU) and eniluracil (Glaxo Wellcome Inc.,Research Triangle Park, North Carolina), an inactivator of dihydropyrimidinedehydrogenase (DPD). The rationale for developing a combined eniluracil/5-FUformulation oral dosing form is to simplify treatment with these agents, whichhas been performed using separate dosing forms, and decrease the probabilityof severe toxicity and/or suboptimal therapeutic results caused byinadvertently high or conversely insufficient 5-FU dosing. Patients and methods:The trial was a randomized, three-waycrossover bioequivalence study of three oral dosing forms of eniluracil/5-FUtablets in adults with solid malignancies. Each period consisted of two daysof treatment and a five- to seven-day washout phase. Eniluracil at a dose of20 mg, which results in maximal DPD inactivation, was administered twice dailyon the first day and in the evening on the second day of each of the threetreatments. On the morning of the second day, all patients received a totaleniluracil dose of 20 mg orally and a total 5-FU dose of 2 mg orally as eitherseparate tablets (treatment A) or combined eniluracil/5-FU tablets in twodifferent strengths (2 tablets of eniluracil/5-FU at a strength (mg/mg) of10/1 (treatment B) or 8 tablets at a strength of 2.5/0.25 (treatment C)). Thepharmacokinetics of plasma 5-FU, eniluracil, and uracil, and the urinaryexcretion of eniluracil, 5-FU, uracil, and α-fluoro-β-alanine (FBAL),were studied. To determine the bioequivalence of the combined eniluracil/5-FUdosing forms compared to the separate tablets, an analysis of variance onpharmacokinetic parameters reflecting eniluracil and 5-FU exposure wasperformed. Results:Thirty-nine patients with advanced solid malignancies hadcomplete pharmacokinetic studies performed during treatments A, B, and C. Thepharmacokinetics of eniluracil and 5-FU were similar among the three types oftreatment. Both strengths of the combined eniluracil/5-FU dosing form and theseparate dosing forms were bioequivalent. Mean values for terminal half-life,systemic clearance, and apparent volume of distribution for oral 5-FU duringtreatments A/B/C were 5.5/5.6/5.6 hours, 6.6/6.6/6.5 liters/hour, and50.7/51.5/50.0 liters, respectively. The intersubject coefficient of variationfor pharmacokinetic variables reflecting 5-FU exposure and clearance intreatments ranged from 23% to 33%. The urinary excretion ofunchanged 5-FU over 24 hours following treatments A, B, and C averaged52.2%, 56.1%, and 50.8% of the administered dose of 5-FU,respectively. Parameters reflecting DPD inhibition, including plasma uraciland urinary FBAL excretion following treatments A, B, and C were similar.Toxicity was generally mild and similar following all three types oftreatments. Conclusions:The pharmacokinetics of 5-FU and eniluracil weresimilar and met bioequivalence criteria following treatment with the separateoral formulations of 5-FU and eniluracil and two strengths of the combinedformulation. The availability of a combined eniluracil/5-FU oral dosing formwill likely simplify dosing and decrease the probability of severe toxicityor suboptimal therapeutic results caused by an inadvertent 5-FU overdose orinsufficient 5-FU dosing in the case of separate oral formulations, therebyenhancing the overall feasibility and therapeutic index of oral 5-FU therapy.