Lopinavir/ritonavir combined with twice-daily 400 mg indinavir: pharmacokinetics and pharmacodynamics in blood, CSF and semen.
OBJECTIVE
To evaluate the steady-state blood plasma (BP), CSF and seminal plasma (SP) pharmacokinetics (PK) of twice-daily indinavir 400 mg and lopinavir/ritonavir.


METHODS
Ten HIV-1-positive men on lopinavir/ritonavir participated in a PK study. PK sampling was performed before and 2 weeks after adding indinavir to lopinavir/ritonavir-containing regimens. BP, CSF and SP RNA levels, CD4 counts and blood chemistry were checked at baseline and 2 weeks after indinavir.


RESULTS
At baseline: lopinavir parameters (n=10) in BP were within expected levels. Median lopinavir trough concentrations (n=5) in CSF and SP were below the limit of detection (BLD) (i.e. <10 ng/mL) and 248 ng/mL (range 96-2777), respectively. After indinavir: lopinavir C(max), C(min) and AUC(0-12) increased by 9%, 46% and 20%, respectively (P<0.32, P<0.32 and P<0.20). In two of four men lopinavir concentrations in CSF were detectable at 27 and 29 ng/mL. Median SP lopinavir concentration was 655 ng/mL (20-2734). Median indinavir PK parameters were C(max) 3365 ng/mL (range 2130-5194), C(min) 293 ng/mL (14-766), T(max) 2.25 h (1-3), AUC(0-12) 22452 ng/mL.h (11243-33661), and t(1/2) 2.8 h (1.4-3.7). Median indinavir concentrations in CSF and SP were 39 ng/mL (21-86) and 592 ng/mL (96-983). Two of eight men who initially had detectable BP viral load (VL) became BLD (<50 copies/mL) after the addition of indinavir, and in 2/4 men with low-level viraemia in SP (BPVL BLD) their SPVL became BLD after addition of indinavir.


CONCLUSIONS
Adding indinavir 400 mg twice daily to lopinavir/ritonavir-containing regimens did not significantly alter the median lopinavir PK parameters. However, wide interpatient variability in lopinavir concentrations was seen. In contrast plasma indinavir levels were >80 ng/mL in seven of eight plasma samples, and all CSF and semen samples collected.
Isaac
Adil
A
Hawthorne House, Department of Genitourinary Medicine, Birmingham Heartlands Hospital, Birmingham B9 5SS, UK. Adilisaac@yahoo.com
Taylor
Stephen
S
Cane
Patricia
P
Smit
Erasmus
E
Gibbons
Sarah E
SE
White
David J
DJ
Drake
Susan M
SM
Khoo
Saye
S
Back
David J
DJ
D000328:Adult; D019540:Area Under Curve; D018791:CD4 Lymphocyte Count; D002851:Chromatography, High Pressure Liquid; D004338:Drug Combinations; D015658:HIV Infections / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D015497:HIV-1 / Q000378:metabolism; D006801:Humans; D019469:Indinavir / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D061466:Lopinavir; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D011744:Pyrimidinones / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D012367:RNA, Viral / Q000096:biosynthesis; D012661:Semen / Q000378:metabolism*; D019562:Viral Load
D004338:Drug Combinations; D017320:HIV Protease Inhibitors; D011744:Pyrimidinones; D012367:RNA, Viral; D061466:Lopinavir; D019469:Indinavir