Cerebrospinal fluid abacavir concentrations in HIV-positive patients following once-daily administration.

Abacavir is a widely used nucleotide reverse transcriptase inhibitor, for which cerebrospinal fluid (CSF) exposure has been previously assessed in twice-daily recipients. We studied abacavir CSF concentrations in 61 and nine HIV-positive patients taking abacavir once daily and twice daily, respectively. Patients on once-daily abacavir had higher plasma and CSF concentrations (96 vs. 22 ng ml-1 , P = 0.038 and 123 vs. 49 ng ml-1 , P = 0.038) but similar CSF-to-plasma ratios (0.8 vs. 0.5, P = 0.500). CSF abacavir concentrations were adequate in patients receiving once-daily treatment.

Population pharmacokinetics of abacavir in plasma and cerebrospinal fluid.

The distribution of abacavir into the cerebrospinal fluid (CSF) was assessed by use of a population pharmacokinetic analysis. Plasma and CSF abacavir concentrations in 54 subjects were determined. The abacavir CSF/plasma ratio averaged 36% and increased throughout the dose interval. Abacavir penetrates into the CSF in adequate concentrations to inhibit local human immunodeficiency virus replication.

High-performance liquid chromatographic assay for abacavir and its two major metabolites in human urine and cerebrospinal fluid.

A simple, reversed-phase HPLC assay has been developed and validated to measure the HIV-1 reverse transcriptase inhibitor abacavir and its two major metabolites, a 5'-glucuronide and a 5'-carboxylate, in human urine and cerebrospinal fluid. Sample preparation involved centrifuging to minimize particulates, then diluting the supernatant before HPLC separation and ultraviolet detection at 295 nm. The method described was used successfully to measure concentrations of abacavir and its two major metabolites in urine and cerebrospinal fluid from HIV-1 infected subjects.

Transport characteristics of the anti-human immunodeficiency virus nucleoside analog, abacavir, into brain and cerebrospinal fluid.

The role of the blood-brain and blood-cerebrospinal fluid (CSF) barriers in the distribution of anti-human immunodeficiency virus (HIV) drugs is integral to the design of effective treatment regimens for HIV infection within the brain. Abacavir (formerly 1592U89) is a nucleoside analog reverse transcriptase inhibitor, which has activity against HIV. The ability of this drug to reach the brain at therapeutic concentrations has been explored by means of an established bilateral in situ brain perfusion model in combination with high-performance liquid chromatography analysis in the anesthetized guinea pig. The influence of other drugs on the entry of abacavir into the brain was also investigated and is of special significance with the use of three of more anti-HIV drugs as the recommended treatment for HIV infection. The results of this study indicate that intact [(14)C]abacavir can cross the blood-brain and blood-CSF barriers and enter the brain and cisternal CSF. Further studies, at a perfusion time of 10 min, revealed that the uptake (R(cerebrum)) of this (14)C-labeled drug (10.1 +/- 0.6%) was not affected by the presence of 0.86 to 200 microM unlabeled abacavir (6.8 microM; 11.0 +/- 1.4%), the nucleoside transport inhibitor [10 microM 6-(4-nitrobenzyl)thio-9-beta-D-ribofuranosylpurine; 9.7 +/- 3.3%], or a substrate for the nucleobase transporter (100 microM adenine; 12.7 +/- 3.0%). This would suggest that the entry of abacavir into the brain would not be affected by the presence of other anti-HIV drugs. The results of this animal study indicate that abacavir would be a useful addition to a treatment regimen against HIV-infection within the brain.

Multiple-dose pharmacokinetics and pharmacodynamics of abacavir alone and in combination with zidovudine in human immunodeficiency virus-infected adults.

Abacavir (1592U89) is a nucleoside reverse transcriptase inhibitor with potent activity against human immunodeficiency virus type 1 (HIV-1) when used alone or in combination with other antiretroviral agents. The present study was conducted to determine the multiple-dose pharmacokinetics and pharmacodynamics of abacavir in HIV-1-infected subjects following oral administration of daily doses that ranged from 600 to 1,800 mg, with and without zidovudine. Seventy-nine subjects received abacavir monotherapy for 4 weeks (200, 400, or 600 mg every 8 hours [TID] and 300 mg every 12 h [BID]) and thereafter received either zidovudine (200 mg TID or 300 mg BID) or matching placebo with abacavir for 8 additional weeks. Pharmacokinetic parameters were calculated for abacavir after administration of the first dose and at week 4 and for abacavir, zidovudine, and its glucuronide metabolite at week 12. The concentrations of abacavir in cerebrospinal fluid were determined in a subset of subjects. Steady-state plasma abacavir concentrations were achieved by week 4 of monotherapy and persisted to week 12. At steady state, abacavir pharmacokinetic parameters (area under the plasma concentration-time curve for a dosing interval [AUC(tau)] and peak concentration [C(max)]) were generally proportional to dose over the range of a 600- to 1,200-mg total daily dose. Coadministration of zidovudine with abacavir produced a small and inconsistent effect on abacavir pharmacokinetic parameters across the different doses. At the clinical abacavir dose (300 mg BID) zidovudine coadministration had no effect on the abacavir AUC(tau), which is most closely associated with efficacy. Zidovudine pharmacokinetics appeared to be unaffected by abacavir. Statistically significant but weak relationships were found for the change in the log(10) HIV-1 RNA load from the baseline to week 4 versus total daily AUC(tau) and C(tau) (P < 0.05). The incidence of nausea was significantly associated with total daily AUC(tau) and C(max). In conclusion, abacavir has predictable pharmacokinetic characteristics following the administration of multiple doses.

Transport of alovudine (3'-fluorothymidine) into the brain and the cerebrospinal fluid of the rat, studied by microdialysis.

Extracellular unbound concentrations of alovudine were sampled by microdialysis in order to study the transport of alovudine between the blood and the brain and the cerebrospinal fluid (CSF) in the rat. The AUC (area under the curve) ratio CSF/blood was higher than the brain/blood ratio after i.v. infusion of alovudine 25mg/kg/hr after a loading dose of 25 mg/kg in 5 minutes (n=4). Neither i.v. infusion of thymidine (25 mg/kg/hr, n=5; 100 mg/kg/hr, n=2) nor acetazolamide (50 mg/kg i.p. bolus followed by 25 mg/kg i.p. every second hour, n=3) influenced the brain/blood AUC ratio after alovudine 25 mg/kg s.c. injection compared to controls (n=5). Finally, perfusion through the microdialysis probe with thymidine (1000 microM, n=3) had also no effect on the brain/blood AUC ratio after alovudine 25 mg/kg s.c. Because neither thymidine nor acetazolamide has significant influence on the ability of alovudine to penetrate the blood-brain barrier in the rat, neither thymidine transport nor carboanhydrase dependent CSF production appear to be major determinants of the blood-brain concentration gradient. Thus, it is concluded that alovudine reaches the extracellular fluid of the brain not by cerebrospinal fluid, but via the cerebral capillaries and that the existence of a concentration gradient over both blood-brain and CSF-brain barrier can probably be explained by the presence of an active process pumping alovudine out from the brain.

Pharmacokinetics of [(14)C]abacavir, a human immunodeficiency virus type 1 (HIV-1) reverse transcriptase inhibitor, administered in a single oral dose to HIV-1-infected adults: a mass balance study.

Abacavir (1592U89) ((-)-(1S, 4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene- 1-m ethanol) is a 2'-deoxyguanosine analogue with potent activity against human immunodeficiency virus (HIV) type 1. To determine the metabolic profile, routes of elimination, and total recovery of abacavir and metabolites in humans, we undertook a phase I mass balance study in which six HIV-infected male volunteers ingested a single 600-mg oral dose of abacavir including 100 microCi of [(14)C]abacavir. The metabolic disposition of the drug was determined through analyses of whole-blood, plasma, urine, and stool samples, collected for a period of up to 10 days postdosing, and of cerebrospinal fluid (CSF), collected up to 6 h postdosing. The radioactivity from abacavir and its two major metabolites, a 5'-carboxylate (2269W93) and a 5'-glucuronide (361W94), accounted for the majority (92%) of radioactivity detected in plasma. Virtually all of the administered dose of radioactivity (99%) was recovered, with 83% eliminated in urine and 16% eliminated in feces. Of the 83% radioactivity dose eliminated in the urine, 36% was identified as 361W94, 30% was identified as 2269W93, and 1.2% was identified as abacavir; the remaining 15.8% was attributed to numerous trace metabolites, of which <1% of the administered radioactivity was 1144U88, a minor metabolite. The peak concentration of abacavir in CSF ranged from 0.6 to 1.4 microg/ml, which is 8 to 20 times the mean 50% inhibitory concentration for HIV clinical isolates in vitro (0.07 microg/ml). In conclusion, the main route of elimination for oral abacavir in humans is metabolism, with <2% of a dose recovered in urine as unchanged drug. The main route of metabolite excretion is renal, with 83% of a dose recovered in urine. Two major metabolites, the 5'-carboxylate and the 5'-glucuronide, were identified in urine and, combined, accounted for 66% of the dose. Abacavir showed significant penetration into CSF.

Penetration of 3'-amino-3'-deoxythymidine, a cytotoxic metabolite of zidovudine, into the cerebrospinal fluid of HIV-1-infected patients.

The penetration of 3'-amino-3'-deoxythymidine (AMT) into the cerebrospinal fluid (CSF) of HIV-1-infected patients has been investigated. In 23 patients who used zidovudine (ZDV) chronically, CSF and plasma samples were assayed for AMT and ZDV. The influences of time between ZDV oral administration and lumbar puncture, of ZDV dose, and of the medical indication for lumbar puncture based on the concentration of AMT in CSF and on the CSF-plasma concentration ratio were investigated. AMT can be detected in the CSF after oral administration of ZDV; concentrations of AMT in CSF ranged from 0.75 to 4.8 ng/ml (median, 1.7 ng/ml). The median CSF-plasma concentration ratio was 1, and equaled that for ZDV. CSF and plasma concentrations of AMT were approximately threefold higher in patients with cerebral toxoplasmosis; the CSF-plasma concentration ratio remained equal to unity in these cases. This phenomenon might be caused by a pharmacokinetic interaction between AMT and pyrimethamine, sulfadiazine, folinic acid, or a combination of these. The clinical relevance of AMT, especially the possibility of decreased efficacy of ZDV, throughout the body and in the central nervous system, and the involvement of this metabolite in ZDV-induced myelosuppression, remains to be established.

Pharmacokinetics of dideoxypurine nucleoside analogs in plasma and cerebrospinal fluid of rhesus monkeys.

The pharmacokinetics of 2',3'-dideoxyadenosine (ddA), didanosine, 2',3'-dideoxyguanosine (ddG), and 6-halogenated prodrugs of ddG, 6-chloro-ddG and 6-iodo-ddG, in plasma and cerebrospinal fluid (CSF) were studied in a non-human primate model. ddA was rapidly and completely deaminated to didanosine, such that didanosine concentration profiles in plasma and CSF were identical following administration of ddA and didanosine. The mean clearance of didanosine was 0.50 liters/h/kg, the terminal half-life was 1.8 h, and the CSF-to-plasma ratio was 4.8%. The disposition of ddG was similar, with a clearance of 0.70 liters/h/kg and a half-life of 1.7 h. The adenosine deaminase-mediated conversion of the 6-halogenated-ddG prodrugs to ddG was rapid but incomplete (48% for 6-chloro-ddG and 29% for 6-iodo-ddG). The CSF-to-plasma ratios of ddG with equimolar doses of ddG, 6-chloro-ddG, and 6-iodo-ddG were 8.5, 24, and 17%, respectively, but the actual ddG exposures in CSF (area under the CSF concentration-time curve) were comparable for ddG (12.1 microM.h) and the 6-halogenated-ddG prodrugs (18.8 microM.h for 6-chloro-ddG, 9.3 microM.h for 6-iodo-ddG).6-Chloro-ddG was not detectable in plasma or CSF, and the CSF-to-plasma ratio of 6-iodo-ddG was 9.4%, so the higher CSF-to-plasma ratios of ddG with the administration of the 6-halogenated-ddG prodrugs does not appear to be the result of enhanced penetration of the prodrug and subsequent dehalogenation to ddG. The penetration of ddG into CSF exceeds that of didanosine and is enhanced by administration of the 6-halogenated prodrugs, although the mechanism of this enhanced penetration is unclear.

In vivo activity against HIV and favorable toxicity profile of 2',3'-dideoxyinosine.

The purine analog 2',3'-dideoxyinosine (ddI), which has anti-retroviral activity in vitro was administered for up to 42 weeks to 26 patients with acquired immunodeficiency syndrome (AIDS) or severe AIDS-related complex (ARC). Ten of these individuals were AZT-intolerant. Eight dose regimens were studied. The drug was orally bioavailable and penetrated into the cerebrospinal fluid (CSF). Comparatively little evidence of an effect against human immunodeficiency virus (HIV) was seen at the lowest four doses. However, patients in the four highest dose groups (ddI at 1.6 milligrams per kilogram intravenously and then greater than or equal to 3.2 milligrams per kilogram orally at least every 12 hours or higher) had increases in their circulating CD4+ T cells (P less than 0.0005), increased CD4/CD8 T cell ratios (P less than 0.01), and, where evaluable, more than an 80% decrease in serum HIV p24 antigen (P less than 0.05). The patients also had evidence of improved immunologic function, had reduced viremic symptomatology, and gained a mean of 1.6 kilogram with these comparatively infrequent dosing schedules (every 8 or 12 hours). The most notable adverse effects directly attributable to ddI administration at the doses used in this study included increases in serum uric acid (due to hypoxanthine release) and mild headaches and insomnia. These results suggest that serious short-term toxicity at therapeutic doses is not an inherent feature in the profile of agents with clinical anti-HIV activity. Further controlled studies to define the safety and efficacy of this agent may be worth considering.