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An open-label multicentre pilot study evaluating the pharmacokinetics (PK) of co-administered lopinavir (LPV) and nevirapine (NVP) in HIV+ adults

  • 1,
  • 2,
  • 2,
  • 3,
  • 4,
  • 5,
  • 4,
  • 1,
  • 2,
  • 1 and
  • 2
Journal of the International AIDS Society200811 (Suppl 1) :P250

https://doi.org/10.1186/1758-2652-11-S1-P250

  • Published:

Keywords

  • Nevirapine
  • Trough Concentration
  • Tablet Formulation
  • Lopinavir
  • Geometric Mean Ratio

Purpose of the study

Co-administration of LPV/r SGC with NVP, an inducer of CYP3A, necessitates a LPV/r dose increase. The objectives of "The NRTI Sparing Study" were to evaluate the PK of co-administered LPV/r and NVP in HIV-infected subjects at week 4 and to assess any changes in these PK parameters at 48 weeks follow-up.

Methods

In this prospective, 48-week (wk), multicentre study, 40 patients (39 ART-naive) were recruited to receive LPV/r SGC (533/133 mg BID) plus NVP (200 mg BID) and undergo PK sampling (0–12 hr) at wk 4 and wk 48. In one of the two participating centres, switches to the LPV/r tablet formulation (400/100 mg BID) were allowed between wk 4 and 48, once HIV-RNA was <50 copies/ml. LPV concentrations were determined by HPLC-MS/MS and NVP concentrations via HPLC-UV. PK parameters were calculated via non-compartmental analysis and within-subject changes assessed by geometric mean ratios (GMR) with 95% confidence intervals (95% CI).

Summary of results

Wk 4 PK data were available on 35 patients. Geometric mean (95% CI) LPV AUC and C were 92012 ng.h/ml (81237–104215) and 3979 ng/ml (3159–5011), respectively. For NVP these values were 62749 ng.h/ml (55621–70790) and 4594 ng/ml (4023–5246), respectively. At wk 24, five individuals had HIV-RNA >50 copies/ml. Wk 4 PK data was available on 4/5 of these patients, all of whom had LPV and NVP concentrations greater than the proposed trough concentration desirable in patients with wild-type HIV-1 (1000 and 3000 ng/ml, respectively). Twenty-five patients also underwent wk 48 PK sampling; of these 10 remained on SGC, while 15 switched to the tablet formulation (400/100 mg BID). No significant intra-individual changes in PK were observed over 48 wks for patients remaining on SGC (p > 0.24). In those switching to the tablet, PK parameters were not significantly different (p > 0.68), although there was a trend towards lower LPV C at wk 48 (see Table 1).

Table 1

PK [patients remaining on LPV/r SGC (n = 10)]

Wk 4

Wk 48

GMR (95% CI)

CV% wk 4; wk 48

LPV AUC0–12, ng.h/ml

102951 (85318, 130692)

91589 (84050, 101101)

0.89 (0.70, 1.13)

34; 15

LPV Ctrough, ng/ml

4848 (3615, 7952)

5230 (4347, 6794)

1.08 (0.67, 1.75)

60; 35

LPV Cmax, ng/ml

12307 (10659, 14663)

11115 (10209, 12251)

0.90 (0.75, 1.08)

26; 15

NVP AUC0–12, ng.h/ml

71850 (67089, 90850)

68793 (58059, 86236)

0.96 (0.83, 1.10)

45; 33

NVP Ctrough, ng/ml

5254 (4933, 6676)

4932 (4032, 6527)

0.94 (0.76, 1.16)

45; 40

NVP Cmax, ng/ml

6924 (6440, 8741)

6830 (5846, 8385)

0.99 (0.85, 1.15)

46; 30

PK [patients switching to LPV/r tablet (n = 15)]

Wk 4

Wk 48

GMR (95% CI)

CV% wk 4; wk 48

LPV AUC0–12, ng.h/ml

77332 (68401, 87428)

67853 (60277, 85324)

0.88 (0.67, 1.14)

26; 34

LPV Ctrough, ng/ml

3171 (2355, 4271)

2164 (2013, 3688)

0.68 (0.37, 1.24)

62; 58

LPV Cmax, ng/ml

9393 (8619, 10518)

8706 (7618, 10846)

0.93 (0.76, 1.12)

20; 35

NVP AUC0–12, ng.h/ml

55289 (49589, 64356)

57231 (50758, 64528)

1.04 (0.88, 1.21)

26; 26

NVP Ctrough, ng/ml

3984 (3842, 4947)

4063 (3540, 4665)

1.02 (0.86, 1.21)

28; 29

NVP Cmax, ng/ml

5447 (4918, 6251)

5576 (5004, 6469)

1.02 (0.88, 1.20)

24; 25

Values given as geometric mean (95% CI); CV% = coefficient of variation (%).

Conclusion

This study explored an NRTI sparing strategy. We recognise that one limitation is that some patients were switched to the LPV/r tablet formulation. The issue of whether, if starting with this strategy, a dose of 400/100 mg or 600/150 mg tablet would be used, has not been addressed here. PK parameters at wk 4 and 48 did not differ significantly in patients receiving co-administered LPV/r and NVP. However, there was a trend towards lower LPV C in patients who switched to LPV/r tablet. Therefore, there is a need for caution and a consideration for TDM-guided dose adjustment depending on the population.

Authors’ Affiliations

(1)
Department of Pharamcology and Therapeutics, University of Liverpool, Liverpool, UK
(2)
Department of HIV Medicine, Royal Free NHS Trust, London, UK
(3)
Department of Primary Care and Population Sciences, Royal Free and UCL Medical School, London, UK
(4)
Copenhagen HIV Programme (CHIP), Copenhagen, Denmark
(5)
St George's Hospital, London, UK

Copyright

© Else et al; licensee BioMed Central Ltd. 2008

This article is published under license to BioMed Central Ltd.

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