Stavudine entry into cerebrospinal fluid after single and multiple doses in patients infected with human immunodeficiency virus.
OBJECTIVE
To establish the pharmacokinetics of stavudine within the cerebrospinal fluid (CSF) of patients infected with human immunodeficiency virus (HIV).


METHODS
Pharmacokinetic study.


METHODS
General clinical research center.


METHODS
Thirty-six patients infected with HIV; 21 were receiving long-term stavudine therapy, 15 were not (single-dose treatment group).


METHODS
After an overnight fast, all patients received a single dose of stavudine 40 mg. Fifteen patients in the long-term treatment group and all 15 patients in the single-dose treatment group were randomized to undergo lumbar puncture 2, 4, or 6 hours after dosing (five patients for each time point from each group). The six other patients in the long-term treatment group underwent lumbar puncture 0 or 8 hours after dosing.


RESULTS
Serum stavudine concentrations were obtained just before dosing, 1 hour after dosing (approximate peak), and at the time of lumbar puncture. The CSF was also analyzed for cell counts, protein, and glucose levels. The mean peak serum stavudine concentration in the long-term treatment group was estimated to be 580.7 ng/ml (2.59 micromol/L), occurring approximately 1.3 hours after dosing. The CSF concentrations over 0-8 hours were 0.0-109.9 ng/ml (0.00-0.49 micromol/L) with an overall mean of 51.6 ng/ml (0.23 micromol/L). Mean peak CSF concentration was estimated to be 62.8 ng/ml (0.28 micromol/L), occurring 4.7 hours after dosing. For the 15 patients not taking stavudine, both the serum and the CSF estimated peaks were significantly lower than those of the long-term group: 475.3 ng/ml (2.12 micromol/L) and 40.4 ng/ml (0.18 micromol/L), respectively. However, time to peak was similar at 1.2 hours and 5.0 hours, respectively. In both groups, no correlation was found between CSF and baseline or peak serum stavudine concentrations, CSF white blood cell count, baseline CD4 + lymphocyte count, or plasma viral load.


CONCLUSIONS
Mean CSF stavudine concentrations equaled or exceeded the mean concentration producing 50% of the maximal effect in vivo (EC 50 ) for HIV. The CSF concentrations were higher in the stavudine-experienced patients, indicating that concentrations rise with progressive doses until steady state is reached.
Brady
Kathleen A
KA
Infectious Diseases Division, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Boston
Ray C
RC
Aldrich
Jennifer L
JL
MacGregor
Rob Roy
RR
D000328:Adult; D018791:CD4 Lymphocyte Count / Q000379:methods; D004334:Drug Administration Schedule; D005260:Female; D005947:Glucose / Q000134:cerebrospinal fluid; D015658:HIV Infections / Q000134:cerebrospinal fluid* / Q000175:diagnosis / Q000188:drug therapy*; D006801:Humans; D007958:Leukocyte Count / Q000379:methods; D008297:Male; D011506:Proteins / Q000737:chemistry; D018119:Stavudine / Q000008:administration & dosage / Q000134:cerebrospinal fluid* / Q000493:pharmacokinetics*; D013997:Time Factors
D011506:Proteins; D018119:Stavudine; D005947:Glucose