Pharmacology and drug interaction studies in adults: summary table from CROI, ICAAC and EACS conferences
Simon Collins, HIV i-Base
The following table includes summaries of non-pregnant adult PK and drug-drug interaction studies from the three most recent major HIV conferences: 13th CROI, 45th ICAAC and 10th EACS.
Studies relating to pharmacology during pregnancy are covered in separate reports in this issue of HTB and the paediatric studies will be included in the May edition of HTB.
All abstracts are available online at the respective conference websites. Abstracts from EACS and CROI are also archived on the AEGiS.org conference database. ICAAC abstracts are usually removed from any public online access several months after the conference.
Please consult abstracts for full study for details.
The 13th Conference on Retroviruses and Opportunistic Infections
45th Annual International Conference on Antimicrobial Agents and Chemotherapy (ICAAC)
The 10th European AIDS Conference/EACS
HIV / AIDS Information on the Internet, provided by AEGIS
Table 1: PK and drug interaction studies at CROI, ICAAC and EACS
|ARVs, PK and absorption|
|TMC-114/r||Food||AUC and Cmax TMC-114 ↑ by >30%||Take with food. Type of food not important|| Sekar V et al. 10th EACS. PE4.1/1|
|TMC-114/r||Atazanavir 300mg||ATV pre dose 875 ↑ RTV AUC 50% ↑ ATZ AUC → TMC-114/r →||TMC-114/r and ATZ can be taken together if needed. Caution for RTV toxicity. ATZ and TMC-114 AUCs unchanged.|| Boffito M et al. 13th CROI. Abstract 575c|
|TMC-114||TMC-125||TMC-125 ↓ AUC reduced by nonsignificant 30% TMC114/r →||No clinically significant interaction|| Boffito M et al. 13th CROI. Abstract 575c.|
|TMC-125 800mg BID||Tipranavir 500mg/ritonavir 200mg BID||TMC-125 ↓↓↓ AUC reduced by 76%. Cmax reduced by 71%. Cmin reduced by 82%.||TMC-125 should NOT be given with tipranavir/r|| Scholler et al. 13th CROI. Abstract 583|
|TMC-278 (NNRTI in development)||Lopinavir/r||TMC-278 AUC ↑ 150% Cmin ↑ 174%|| Hoetelmans R et al. 10th EACS. Abstract PE4.3/1|
|Meltrex Kaletra (lopinavir/r) 3 x Meltrex BID (600mg/150mg) vs 2 x Meltrex BID (200mg/100mg)||Efavirenz 600mg QD||LPV ↑ 36% RTV ↑ 78% (compared to 2 x 400mg/100mg Meltrex Kaletra)||Use 600mg/150mg BID when dosing with EFV in experienced pts. Use 400mg/100mg BID when dosing with EFV in naive pts.|| Klein C et al. 10th EACS. Abstract PE4.3/2|
|PPIs and H2 blockers|
|Saquinavir/r 1000mg/100mg BID||Omeprazole 40mg (proton pump inhibitor/gastric pH modifier)||SQV Cmax AUC ↑ 77%
SQV AUC ↑ 82%
|No dose adjustment recommended
Caution for increased GI side effects
| Winston A et al.10th EACS.Abstract LBPE4.3/16.|
|Meltrex Kaletra (lopinavir/r)||Omeprazole (Proton pump inhibitor)
|LPV/r → Omeprazole →||No interaction|| Klein C et al.
13th CROI. Abstract 578.
|Meltrex Kaletra (lopinavir/r)||Ranitidine 150mg single dose
|LPV/r → Ranitidine →||No interaction|| Klein C et al.
13th CROI. Abstract 578.
|Atazanavir 400mg QD||Lansoprazole 60mg QD||Atazanavir ↓↓↓
ATZ AUC reduced by 95%.
|ATV should NOT be given with lansoprazole|| Tomilo DL et al.
45th ICAAC. Abstract A-1192
|Atazanavir 300mg/ ritonavir 100mg QD||Rifampin 300mg QD||Atazanavir ↓↓↓
ATZ Cmax, C min and AUC all undetectable. Study stopped after 3 patients.
|ATZ should NOT be given with rifampicin.
RTV boosting doesn’t overcome interaction.
| Mallolas J et al. 45th ICAAC. Abstract A-1202|
|Fosamprenavir 700mg/ritonavir 100mg BID||Rifabutin 150mg||Rifabutin ↑↑
Crossover study showed lower dose RIF maintains similar rifabutin levels
|Reduce rifabutin dose from 300mg QD to 150mg QD|| Chen Y et al. 45th ICAAC. Abstract A-1199|
|Nevirapine (single 200mg dose)||Rifampicin
Standard weight-based dose
|Nevirapine ↓↓ Cmax by 20% Ctrough by 60% AUC by 80% T1/2 by 66%||Nevirapine should NOT be given with rifampicin|| Pujari S et al.
13th CROI. Abstract 574.
|Lopinavir/r Standard dose||Rosuvastatin
10mg, 20mg and 40mg used in study
|LPV/r → RSV increased by 150-200%||Further study required – compared results to historical data.|| Van der Lee M et al.
13th CROI. Abstract 588.
|Nelfinavir 1250mg BD||Pravastatin 40mg QD||NFV AUC ↓ 46% PVS Cmax ↓ 40%||Pravastatin dose may need to be increased.|| Alberb J et al.
AIDS 2006; 20:725- 729.
|Efavirenz 600mg QD||Carbamazepine (anticonvulsant)
200mg and 400mg doses QD studied
|Efavirenz ↓ Carbamazepine↓||Both EFV and CBZ levels are reduced. Lack of data mean no dose recommendation can be made. Use of alternate anticonvulsants may be necessary.|| Kaul S et all
13th CROI. Abstract 575a
|Lopinavir/r||CYP2D6 metabolised drugs||CYP2D6 activity ↓ 50%
dextromethorphan ↑ 300%
|Caution for increased levels of drugs metabolised by CYP2D6, which include antidepressants (including risperidone), antipsychotics, beta blockers and MDMA (Ecstacy)|| Wyen C et al.
10th EACS. Abstract PE4.1/6.
BID = twice-daily; QD = once-daily
The food interaction study with TMC114 was well designed with a specific range of different options.
Although it is likely that TMC114 will be recommended to ‘take with food’ it is useful to know that ‘coffee and croissant’ is sufficient.
The interaction between the Meltrex formulation of lopinavir/r (Kaletra) and efavirenz is the first time that NNRTIs have been shown to increase levels of a PI. This is interesting, although patient variability may make this positive interaction less reliable in an individual patient, hence the recommendation to increase the Meltrex dose in treatment experienced patients.
The interaction between lopinavir/r (Kaletra) which increased rosuvastatin by 150-200% was unexpected as rosuvastatin is not mediated by CYP 3A4 pathway. This highlights the importance of real in vivo interaction studies, and the limitations of recommendations based only on a theoretical likelihood of an interaction.
- Sekar V et al. The effects of different meal types on the PK of TMC114 tablet formulation dosed with ritonavir in healthy volunteers. 10th European AIDS Conference. November 17-20, 2005. Dublin. Abstract PE4.1/1.
- Sekar V et al. Pharmacokinetc interraction between TMC114/ritonavir and atazanavir in healthy volunteers. 10th European AIDS Conference.November 17-20, 2005. Dublin. PE 4.3/4.
- Boffito M, Winston A, Fletcher C et al. Pharmacokinetics and ART response to TMC114/r and TMC125 combination in patients with high-level viral resistance. Abstract 575c.
- Scholler et al. Significant decrease in TMC125 exposures when co-administered with tipranavir boosted with ritonavir in healthy subjects. 13th CROI. Abstract 583.
- Hoetelmans R et al. Pharmacokinetic interaction between TMC278, and investigational NNRTI and lopinavir/r in healthy volunteers. 10th EACS. Abstract PE4.3/1.
- Klein C, Zhu T, Chiu YL, et al. Effect of efavirenz on lopinavir/ritonavir pharmacokinetics from a new tablet formulation. 10th European AIDS Conference. November 17-20, 2005. Dublin. Abstract PE4.3/2.
- Winston A, Back D, Fletcher C, et al. Effect of omeprazole on the pharmacokinetics of saquinavir 500 mg formulation with ritonavir in healthy male and female volunteers. 10th European AIDS Conference. November 17-20, 2005. Dublin. Abstract LBPE4.3/16.
- Klein C et al. Lack of effect of acid-reducing agents on the pharmacokinetics of lopinavir/ritonavir tablet. 13th CROI. Abstract 578.
- Tomilo et al. The effect of lansoprazole acid suppression on the pharmacokinetics of atazanavir in healthy volunteers. 45th ICAAC. Abstract A-1192.
- Mallolas J et al. Pharmacokinetic interaction between rifampin and the combination of atazanavir and low dose ritonavir in HIV-infected patients. 45th ICAAC. Abstract A-1202.
- Chen Y et al. Pharmacokinetic interaction between rifabutin (RFB) and fosamprenavir (FPV)/ritonavir (RTV) in healthy subjects. 45th ICAAC. Abstract A-1199.
- Pujari S et al. Effect of rifampin hepatic induction on nevirapine levels in Indian volunteers. 13th CROI. Abstract574.
- Van Der Lee M et al Pharmacokinetics and pharmacodynamics of combined use of lopinavir/ritonavir and rosuvastatin in HIV-infected patients. 13th CROI. Abstract 588
- Judith A. Aberg, Susan L. Rosenkranz, Carl J. Fichtenbaum, Beverly L. Alston, Susan W. Brobst, Yoninah Segal, John G. Gerber, for the
ACTG A5108 team. Pharmacokinetic interaction between nelfinavir and pravastatin in HIV-seronegative volunteers: ACTG Study A5108. AIDS 2006;20:725-729.
- Kaul S et al A 2-way pharmacokinetic interaction between efavirenz and carbamazepine. 13th CROI. Abstract 575a.
- Wyen C, Jetter A, Frank D, et al. CYP2D6 is inhibited by lopinavir/ritonavir in HIV-infected patients. European AIDS Conference. November 17-20, 2005. Dublin. Abstract PE4.1/6