Aims The purpose of this study was to investigate the pharmacokinetics of a single oral dose of lamivudine administered to subjects with renal impairment and to determine whether lamivudine was dialysable in subjects with severe renal impairment undergoing haemodialysis. Methods Twenty-nine subjects were enrolled, nine with normal renal function (creatinine clearance (CL CR ) 82-117 ml min −1 ), eight with moderately impaired renal function (CL CR 25-49 ml min −1 ), six with severe impairment (CL CR 13-19 ml min −1 ) and six with severe impairment who were also receiving haemodialysis. After an overnight fast, nondialysis subjects received a single oral dose of lamivudine. Subjects on haemodialysis were given two doses on separate occasions (intra and interdialysis). Blood was obtained before lamivudine administration and at regular intervals to 48 h post dose. Timed urine collections were performed for subjects able to produce urine. Pharmacokinetic parameters were calculated by using standard non compartmental techniques. Results Decreasing renal function was associated with reduced lamivudine clearance in a proportional and apparently linear relationship. Lamivudine was well dialysed with an extraction ratio in the order of 50%. However, because lamivudine has a large volume of distribution (#100 l), a haemodialysis session of 4 h did not affect overall exposure to a clinically significant degree in most subjects. Conclusions Impaired renal function does require lamivudine dose modification according to the degree of impairment, but no further modification of dose is required for subjects undergoing regular haemodialysis.

2-Deoxy-3-thiacytidine is a dideoxycytidine analog with a sulfur in place of the 3 carbon of the ribose. There are two enantiomeric forms of the compound, both of which inhibit human immunodeficiency virus type 1 and 2 replication in vitro. However, the (؊) enantiomer (lamivudine) appears to be significantly less cytotoxic to uninfected lymphocytes than is the (؉) enantiomer. Lamivudine has entered initial clinical trials, and the present study was designed to describe the pharmacokinetic behavior of this compound in both plasma and cerebrospinal fluid (CSF) of primates. Lamivudine was administered as an intravenous bolus dose of 20 mg/kg to five nonhuman primates, and plasma and CSF (ventricular and lumbar) were sampled at frequent intervals for 24 h after administration. Urine samples were also obtained from two animals. The same dose of the racemate (BCH-189) was administered to one animal. The drug was quantitated in CSF and plasma with a reverse-phase high-pressure liquid chromatography technique. Elimination of lamivudine from plasma was biexponential, with a mean alpha phase half-life of 5.4 min, a mean beta phase half-life of 84 min, and a total clearance of 6.1 liters/h. The total clearance of the same dose of BCH-189 in a single animal was 11.0 liters/h. In two animals from which urine was obtained for 12 h postadministration, 32 and 59% of the drug was recovered unchanged. The deamination product of lamivudine was not detected. The CSF/plasma ratio of lamivudine was significantly higher when the drug was measured in the lumbar CSF (mean, 0.41) than when it was measured in the ventricular CSF (mean, 0.079). The measured CSF/plasma ratio for ventricular CSF is equivalent to that of other dideoxycytidine analogs, confirming the importance of the nucleobase in determining the degree of CSF penetration. The difference in lamivudine exposure in ventricular and lumbar CSF suggests that there is a transport mechanism for efflux of cytidine analogs from ventricular CSF.Lamivudine, the (Ϫ) enantiomer of 2Ј-deoxy-3Ј-thiacytidine, is a dideoxynucleoside analog in which the 3Ј carbon of the ribose of 2Ј,3Ј-dideoxycytidine (ddC) is replaced by a sulfur (Fig. 1). (1). Both the (Ϫ) and (ϩ) enantiomers of 2Ј-deoxy-3Ј-thiacytidine have been shown to inhibit in vitro replication of human immunodeficiency virus types 1 and 2. However, in preclinical studies lamivudine appeared to be significantly less cytotoxic to uninfected lymphocytes than did the (ϩ) enantiomer (3). On the basis of the in vitro antiretroviral activity and the relative lack of cytotoxicity of lamivudine, phase I/II clinical trials of this agent with both children and adults have been initiated (5,9,12,16).The cerebrospinal fluid (CSF) penetration of several other pyrimidine dideoxynucleosides, including zidovudine and ddC, has been studied in a nonhuman primate model. These studies suggest that the degree of CSF penetration is dependent upon the nucleobase rather than the structural changes to the sugar moiety. In the present study, the plasma and CSF ...

PurposeThe practice of intentional rounding up of serum creatinine (SCr) in elderly patients with low measured values can lead to an underestimation of creatinine clearance and subsequent inaccurate dosing of medications. Thus, the purpose of this study was to evaluate the accuracy of vancomycin dose calculations for patients aged ≥65 years using an SCr rounded up to 1 mg/dL versus actual SCr.MethodsThis study compared the difference between measured steady-state vancomycin trough concentrations with predicted trough concentrations that have been calculated using rounded SCr and actual SCr. All non-obese patients ≥65 years of age with a baseline SCr <1 mg/dL who received a vancomycin regimen based on a SCr rounded to 1 mg/dL, and had a steady-state trough drawn between June 2014 and December 2015, were evaluated. A total of 1709 patients were evaluated, of whom 56 met all the selection criteria.ResultsThe mean difference between measured vancomycin trough concentrations and predicted trough concentrations using rounded SCr was 8.84 versus 4.54 μg/mL using actual SCr [mean difference 4.31, 95% confidence interval (CI) 3.2–5.41; p < 0.0001]. In female patients, the mean difference between measured concentrations and predicted concentrations using rounded SCr was 9.68 versus 3.53 μg/mL using actual SCr (mean difference 6.15, 95% CI 4.42–7.88; p < 0.0001), while in male patients the mean difference between measured concentrations and predicted concentrations using rounded SCr was 8.21 versus 5.29 μg/mL using actual SCr (mean difference 2.92, 95% CI 1.6–4.24; p < 0.0001).ConclusionUsing actual SCr to perform vancomycin dosing calculations more accurately predicted measured vancomycin troughs than using an SCr rounded to 1 mg/dL. In our sex-specific analysis, using actual SCr resulted in more accurate trough projections for both males and females than using a rounded SCr.

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