Factors influencing lopinavir and atazanavir plasma concentration.
BACKGROUND
The protease inhibitors lopinavir and atazanavir are both recommended for treatment of HIV-infected patients. Considerable inter-individual variability in plasma concentration has been observed for both drugs. The aim of this study was to evaluate which demographic factors and concomitant drugs are associated with lopinavir and atazanavir plasma concentration.


METHODS
Data from the Liverpool TDM (therapeutic drug monitoring) Registry were linked with the UK Collaborative HIV Cohort (CHIC) study. For each patient, the first measurement of lopinavir (twice daily) or atazanavir [once daily, ritonavir boosted (/r) or unboosted] plasma concentration was included. Linear regression was used to evaluate the association of dose, gender, age, weight, ethnicity and concomitant antiretroviral drugs or rifabutin with log-transformed drug concentration, adjusted for time since last intake.


RESULTS
Data from 439 patients on lopinavir (69% 400 mg/r, 31% 533 mg/r; 3% concomitant rifabutin) and 313 on atazanavir (60% 300 mg/r, 32% 400 mg/r, 8% 400 mg) were included. Multivariable models revealed the following predictors for lopinavir concentration: weight (11% decrease per additional 10 kg; P = 0.001); dose (25% increase for 533 mg/r; P = 0.024); and rifabutin (116% increase; P < 0.001). For atazanavir the predictors were dose (compared with 300 mg/r: 40% increase for 400 mg/r, 67% decrease for 400 mg; overall P < 0.001) and efavirenz (32% decrease; P = 0.016) but not tenofovir (P = 0.54).


CONCLUSIONS
This analysis confirms that efavirenz decreases atazanavir concentrations, and there was a negative association of weight and lopinavir concentrations. The strong impact of rifabutin on lopinavir concentration should be studied further.
Stöhr
Wolfgang
W
MRC Clinical Trials Unit, London, UK. ws@ctu.mrc.ac.uk
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David
D
Dunn
David
D
Sabin
Caroline
C
Winston
Alan
A
Gilson
Richard
R
Pillay
Deenan
D
Hill
Teresa
T
Ainsworth
Jonathan
J
Gazzard
Brian
B
Leen
Clifford
C
Bansi
Loveleen
L
Fisher
Martin
M
Orkin
Chloe
C
Anderson
Jane
J
Johnson
Margaret
M
Easterbrook
Philippa
P
Gibbons
Sara
S
Khoo
Saye
S
D000328:Adult; D000480:Alkynes; D019380:Anti-HIV Agents / Q000097:blood* / Q000493:pharmacokinetics*; D000069446:Atazanavir Sulfate; D048588:Benzoxazines / Q000097:blood / Q000493:pharmacokinetics; D001835:Body Weight; D003521:Cyclopropanes; D005260:Female; D015658:HIV Infections / Q000188:drug therapy; D006801:Humans; D061466:Lopinavir; D008297:Male; D008875:Middle Aged; D009842:Oligopeptides / Q000097:blood* / Q000493:pharmacokinetics*; D010949:Plasma / Q000737:chemistry*; D011725:Pyridines / Q000097:blood* / Q000493:pharmacokinetics*; D011744:Pyrimidinones / Q000097:blood* / Q000493:pharmacokinetics*; D017828:Rifabutin / Q000097:blood / Q000493:pharmacokinetics; D006113:United Kingdom
D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D009842:Oligopeptides; D011725:Pyridines; D011744:Pyrimidinones; D017828:Rifabutin; D061466:Lopinavir; D000069446:Atazanavir Sulfate; C098320:efavirenz