Simultaneous population pharmacokinetic model for lopinavir and ritonavir in HIV-infected adults.
BACKGROUND
Lopinavir is a protease inhibitor indicated for the treatment of HIV infection. It is coformulated with low doses of ritonavir in order to enhance its pharmacokinetic profile. After oral administration, plasma concentrations of lopinavir can vary widely between different HIV-infected patients.


OBJECTIVE
To develop and validate a population pharmacokinetic model for lopinavir and ritonavir administered simultaneously in a population of HIV-infected adults. The model sought was to incorporate patient characteristics influencing variability in the drug concentration and the interaction between the two compounds.


METHODS
HIV-infected adults on stable therapy with oral lopinavir/ritonavir in routine clinical practice for at least 4 weeks were included. A concentration-time profile was obtained for each patient, and blood samples were collected immediately before and 1, 2, 4, 6, 8, 10 and 12 hours after a morning lopinavir/ritonavir dose. Lopinavir and ritonavir concentrations in plasma were determined by high-performance liquid chromatography. First, a population pharmacokinetic model was developed for lopinavir and for ritonavir separately. The pharmacokinetic parameters, interindividual variability and residual error were estimated, and the influence of different patient characteristics on the pharmacokinetics of lopinavir and ritonavir was explored. Then, a simultaneous model estimating the pharmacokinetics of both drugs together and incorporating the influence of ritonavir exposure on oral clearance (CL/F) of lopinavir was developed. Population analysis was performed using nonlinear mixed-effects modelling (NONMEM version V software). The bias and precision of the final model were assessed through Monte Carlo simulations and data-splitting techniques.


RESULTS
A total of 53 and 25 Caucasian patients were included in two datasets for model building and model validation, respectively. Lopinavir and ritonavir pharmacokinetics were described by one-compartment models with first-order absorption and elimination. The presence of advanced liver fibrosis decreased CL/F of ritonavir by nearly half. The volume of distribution after oral administration (Vd/F) and CL/F of lopinavir were reduced as alpha1-acid glycoprotein (AAG) concentrations increased. CL/F of lopinavir was inhibited by ritonavir concentrations following a maximum-effect model (maximum inhibition [Imax] = 1, concentration producing 50% of the I(max) [IC50] = 0.36 mg/L). The final model appropriately predicted plasma concentrations in the model-validation dataset with no systematic bias and adequate precision.


CONCLUSIONS
A population model to simultaneously describe the pharmacokinetics of lopinavir and ritonavir was developed and validated in HIV-infected patients. Bayesian estimates of the individual parameters of ritonavir and lopinavir could be useful to predict lopinavir exposure based on the presence of advanced liver fibrosis and the AAG concentration in an individual manner, with the aim of maximizing the chances of treatment success.
Moltó
José
J
"Lluita contra la SIDA" Foundation, Hospital Universitari Germans Trias i Pujol, Badalona, Spain. jmolto@flsida.org
Barbanoj
Manuel José
MJ
Miranda
Cristina
C
Blanco
Asunción
A
Santos
José Ramón
JR
Negredo
Eugenia
E
Costa
Joan
J
Domingo
Pere
P
Clotet
Bonaventura
B
Valle
Marta
M
D000328:Adult; D003430:Cross-Sectional Studies; D004338:Drug Combinations; D005260:Female; D015658:HIV Infections / Q000188:drug therapy / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006801:Humans; D061466:Lopinavir; D008297:Male; D008954:Models, Biological; D011744:Pyrimidinones / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019438:Ritonavir / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use
D004338:Drug Combinations; D017320:HIV Protease Inhibitors; D011744:Pyrimidinones; D061466:Lopinavir; D019438:Ritonavir
Drug Metab Dispos. 2002 Jul;30(7):859-60
12132432
Pharm Res. 2004 Sep;21(9):1622-30
15497688
J Acquir Immune Defic Syndr. 2003 Mar 1;32(3):287-91
12626888
Clin Pharmacol Ther. 2006 Oct;80(4):307-18
17015049
Antivir Ther. 2002 Sep;7(3):165-74
12487383
Br J Clin Pharmacol. 2005 Oct;60(4):378-89
16187970
Antimicrob Agents Chemother. 2002 Sep;46(9):2926-32
12183249
Antimicrob Agents Chemother. 2003 Jan;47(1):350-9
12499212
Br J Clin Pharmacol. 2005 Feb;59(2):174-82
15676039
Hepatology. 2006 Jun;43(6):1317-25
16729309
Br J Clin Pharmacol. 2001 Jan;51(1):99-102
11167671
J Acquir Immune Defic Syndr (1988). 1993 May;6(5):531-3
8097790
Drug Metab Dispos. 2002 Dec;30(12):1455-61
12433819
Antivir Ther. 2004 Aug;9(4):537-43
15456085
Br J Clin Pharmacol. 2005 Apr;59(4):398-404
15801934
Clin Infect Dis. 2003 Jun 15;36(12):1585-92
12802760
Clin Pharmacokinet. 2004;43(5):291-310
15080763
J Pharmacokinet Biopharm. 1981 Aug;9(4):503-12
7310648
AIDS Res Hum Retroviruses. 2004 Mar;20(3):275-8
15117450
Antimicrob Agents Chemother. 2002 Mar;46(3):746-54
11850257
Drug Metab Dispos. 2001 Mar;29(3):299-303
11181499
AIDS. 2002 Oct 18;16(15):2081-3
12370509
Comput Methods Programs Biomed. 1999 Jan;58(1):51-64
10195646
J Antimicrob Chemother. 2003 Mar;51(3):493-6
12615849
J Clin Pharmacol. 2005 Apr;45(4):461-7
15778427
J Acquir Immune Defic Syndr. 2007 Dec 1;46(4):433-42
17786128
J Acquir Immune Defic Syndr. 2007 Jun 1;45 Suppl 1:S5-13; quiz S28-31
17525691
J Infect Dis. 2004 Jan 15;189(2):265-72
14722892
Ther Drug Monit. 2004 Feb;26(1):35-9
14749547
Antimicrob Agents Chemother. 2005 May;49(5):1720-6
15855487
AIDS. 2004 Mar 26;18(5):775-9
15075512
Antivir Ther. 2005;10(8):879-92
16430193
AIDS. 2002 Sep 6;16(13):1743-7
12218384
Antimicrob Agents Chemother. 1998 Dec;42(12):3218-24
9835517
Clin Pharmacokinet. 2007;46(1):85-92
17201460
Ther Drug Monit. 2006 Oct;28(5):650-3
17038880
J Acquir Immune Defic Syndr. 2007 Apr 1;44(4):401-10
17224848
Br J Clin Pharmacol. 2006 Nov;62(5):560-6
17061963
Clin Pharmacokinet. 2005;44(6):591-625
15910009
Br J Clin Pharmacol. 2005 Jul;60(1):32-4
15963091
Ther Drug Monit. 2005 Dec;27(6):782-4
16306855