OBJECTIVE: Protease inhibitors may not penetrate into the central nervous system in therapeutic concentrations, which may allow ongoing HIV replication and injury. The objective of this study was to determine atazanavir penetration into cerebrospinal fluid (CSF). DESIGN: Single random plasma or paired plasma and CSF samples were drawn from participants enrolled in a multicenter, observational cohort study and taking atazanavir with or without ritonavir between October 2003 and October 2005. METHODS: Plasma samples were assayed by high performance liquid chromatography and immunoassay; lower limit of detection was 45 ng/ml. CSF samples were assayed by immunoassay (ARK ATV-test); lower limit of detection was 5 ng/ml. RESULTS: One hundred and seventeen participants (43 +/- 7.7 years, 79% men, 81 +/- 15 kg) had plasma or plasma and CSF paired samples drawn a median (interquartile range) of 10 (5-17) h postdose. Median (interquartile range) plasma atazanavir concentrations with or without ritonavir were 1278 (525-2265) and 523 (283-1344) ng/ml. The median (interquartile range) CSF concentrations with or without ritonavir were 10.3 (<5-21.1) and 7.9 (6.6-22) ng/ml. Nineteen of 79 (24%) CSF samples were less than 5 ng/ml. CSF concentrations were less than 1% of plasma concentrations and near the atazanavir wild-type IC50 of 1-11 ng/ml. CONCLUSION: Atazanavir CSF concentrations are highly variable and 100-fold lower than plasma concentrations, even with ritonavir boosting. CSF concentrations of atazanavir do not consistently exceed the wild-type IC50 of atazanavir and may not protect against HIV replication in the CSF.
OBJECTIVE: Protease inhibitors may not penetrate into the central nervous system in therapeutic concentrations, which may allow ongoing HIV replication and injury. The objective of this study was to determine atazanavir penetration into cerebrospinal fluid (CSF). DESIGN: Single random plasma or paired plasma and CSF samples were drawn from participants enrolled in a multicenter, observational cohort study and taking atazanavir with or without ritonavir between October 2003 and October 2005. METHODS: Plasma samples were assayed by high performance liquid chromatography and immunoassay; lower limit of detection was 45 ng/ml. CSF samples were assayed by immunoassay (ARK ATV-test); lower limit of detection was 5 ng/ml. RESULTS: One hundred and seventeen participants (43 +/- 7.7 years, 79% men, 81 +/- 15 kg) had plasma or plasma and CSF paired samples drawn a median (interquartile range) of 10 (5-17) h postdose. Median (interquartile range) plasma atazanavir concentrations with or without ritonavir were 1278 (525-2265) and 523 (283-1344) ng/ml. The median (interquartile range) CSF concentrations with or without ritonavir were 10.3 (<5-21.1) and 7.9 (6.6-22) ng/ml. Nineteen of 79 (24%) CSF samples were less than 5 ng/ml. CSF concentrations were less than 1% of plasma concentrations and near the atazanavir wild-type IC50 of 1-11 ng/ml. CONCLUSION:Atazanavir CSF concentrations are highly variable and 100-fold lower than plasma concentrations, even with ritonavir boosting. CSF concentrations of atazanavir do not consistently exceed the wild-type IC50 of atazanavir and may not protect against HIV replication in the CSF.
Authors: D W Haas; J Stone; L A Clough; B Johnson; P Spearman; V L Harris; J Nicotera; R H Johnson; S Raffanti; L Zhong; P Bergqwist; S Chamberlin; V Hoagland; W D Ju Journal: Clin Pharmacol Ther Date: 2000-10 Impact factor: 6.875
Authors: Ned Sacktor; Michael P McDermott; Karen Marder; Giovanni Schifitto; Ola A Selnes; Justin C McArthur; Yaakov Stern; Steve Albert; Donna Palumbo; Karl Kieburtz; Joy A De Marcaida; Bruce Cohen; Leon Epstein Journal: J Neurovirol Date: 2002-04 Impact factor: 2.643
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Authors: D W Haas; B W Johnson; P Spearman; S Raffanti; J Nicotera; D Schmidt; T Hulgan; R Shepard; S A Fiscus Journal: Neurology Date: 2003-11-25 Impact factor: 9.910
Authors: David Croteau; Scott Letendre; Brookie M Best; Ronald J Ellis; Sheila Breidinger; David Clifford; Ann Collier; Benjamin Gelman; Christina Marra; Gilbert Mbeo; Allen McCutchan; Susan Morgello; David Simpson; Lauren Way; Florin Vaida; Susan Ueland; Edmund Capparelli; Igor Grant Journal: Antimicrob Agents Chemother Date: 2010-09-27 Impact factor: 5.191
Authors: Ari S Nowacek; Reagan L Miller; Joellyn McMillan; Georgette Kanmogne; Michel Kanmogne; R Lee Mosley; Zhiya Ma; Sabine Graham; Mahesh Chaubal; Jane Werling; Barrett Rabinow; Huanyu Dou; Howard E Gendelman Journal: Nanomedicine (Lond) Date: 2009-12 Impact factor: 5.307