Overview of pharmacology studies

14 September 2005. Related: Conference reports, PK and drug interactions, IAS 3rd Rio de Janeiro 2005.

Dr Steve Taylor and Dr Marta Boffito

www.HIV-druginteractions.org

Set in the capital city of Rio de Janeiro, the 3rd Conference on AIDS Pathogenesis and Treatment yielded little in the way of groundbreaking research; in addition, there were no oral sessions dedicated to HIV Pharmacology.

Only two oral presentations presented pharmacological data. One by Vernazza and colleagues reported the results of the ATARITMO-Study aimed at investigating the pharmacokinetics (PK) and CSF and genital tract penetration in patients on ATV/r boosted monotherapy. [1]

A second oral presentation illustrated the limited inter-individual variability of the new formulation of lopinavir/r developed by Abbott. [2]

However, those with the dedication to navigate the randomly distributed posters were rewarded with a few pearls pertaining to the PK and pharmacodynamics (PD) of new and existing agents.

Reviewing the posters several themes emerged which have been grouped under the following headings:

• Tenofovir interactions and renal toxicity
• Atazanavir inter-patient variability and drug interactions
• Interactions between proton pump inhibitors and protease inhibitors
• PK in pregnancy and liver impairment
• Drug interactions with new and existing drugs
• PK in paediatric patients

Tenofovir interactions and renal toxicity

There were several posters outlining new data regarding the PK/PD of tenofovir (TDF) which helped to clarify some of the complex PK issues surrounding this drug.

In addition the unexpectedly high rate of virological failure seen with the regimen of TDF/ddI 250 mg + EFV was confirmed in a study by Van Lunzen et al. (28% virological failure according to ITT analysis at week 12). [3]

A study by Agarawala and colleagues Investigated the PK effects of the co-administration of TDF and unboosted atazanavir (ATV) at different doses. [4] Two previous studies suggested a bidirectional interaction between ATV and TDF. [5, 6]

Atazanavir concentrations were decreased by 23-28% when co-administered with RTV and TDF in HIV-positive patients, and decreased by 11-20% in HIV-negative volunteers. In addition, TDF concentrations were increased by 29-37%. This study attempted to determine a dosing strategy that would provide ATV and TDF exposures comparable to each drug when dosed alone. The strategies employed were dosing the ATV (400 mg once-daily) and TDF 12 hours apart, and increasing the ATV to 600 mg once-daily. The temporal 12-hour separation of ATV 400 mg once-daily resulted in:

• A decrease in ATV Cmax, AUC, Cmin of 10%, 17%, and 28%, respectively
• An increase in TDF Cmax, AUC and Cmin of 43%, 37%, and 38%, respectively.

The simultaneous administration of 600 mg od ATV with TDF 300 mg resulted in:

• A decrease in ATV Cmax, AUC and Cmin of 27%, 36%, and 41%, respectively
• An increase in TDF Cmax, AUC and Cmin of 41%, 59%, and 74%, respectively.

Based on these findings the authors continue to recommend that when co-dosed with TDF, ATV (300 mg od) should be combined with RTV (100 mg od).

Louie and colleagues investigated the mechanism behind the interaction between low dose RTV containing HAART and TDF in vivo [7] and in vitro. [8]

The in vivo study involved a retrospective database analysis in approximately 1000 patients receiving tenofovir. Serum creatinine (sCr) were higher than 1.5 mg/dL (132 umol/L) in 89 patients (8.8%). However, 44 patients had either a pre-existing sCr >1.5 or hypertension/diabetes. These patients were excluded from the analysis. Therefore, 45 subjects were evaluable and of these 89% were on a PI containing regimen, 84% on a RTV containing regimen, and 76% on LPV/r. Renal toxicity staging observed in the study is shown in the Table 1

Average stage 3.13 – 0.84*

*This corresponds to an average GFR of 44.7-20 mL/min/1.73m²

In conclusion, the study suggested that RTV-boosted regimens containing TDF may predispose patients to renal insufficiency and identified the time to renal events at an average 9 months. This is consistent with case reports cited in the literature. The ethnic breakdown of the patients in this study was representative of the patients in the clinical cohort as a whole (60% Caucasian, 16% Hispanic, and 14% African American). Pharmacogenomic studies to determine the contribution of ethnicity to these findings are warranted.

A potential mechanism for these findings was postulated by authors from the same group by an in vitro analysis utilising a renal epithelial cell lines which over expressed MRP2 (an efflux transporter abundantly expressed on the apical side of the proximal renal epithelial cells, and responsible for the elimination of xenobiotics from the blood to the lumen of the proximal tubule). [8]

TDF alone was not nephrotoxic even at high concentrations. However, when combined with MRP2 inhibitors (LPV=RTV>cyclosporine>MK571), TDF efflux was reduced and intracellular concentrations increased. TDF was phosphorylated to the active form within the cells, causing cellular toxicity at high concentrations. Hence, a potential mechanism for cell damage was postulated.

Atazanavir inter-patient variability and drug interactions

Several posters explored atazanavir (ATV) concentrations when dosed alone and in combination with different doses of RTV. Perhaps the most common thread running through all of these presentations was the large degree of inter-patient variability in ATV concentrations in patients taking the same drug dose.

A French group [9] measured ATV concentrations in 70 patients, 21 on ATV 400 mg once-daily (od), 37 on ATV/RTV 300/100 mg od (including 5 also on NNRTIs) and 7 on ATV/ RTV 400/100 mg od + NNRTI. The median ATV Cmin in the ATV 400 mg and in the 300/100 mg groups were 151 ng/ml (range 35-1159) and 494 ng/ml (range 417-1731), respectively. Overall, there was a 3.3-fold increase in ATV Cmin when boosted with RTV (p<0.001). The induction caused by the use of NNRTIs was associated with a significantly reduced Cmin in the 300/100 mg group. However, use of ATV/RTV 400/100 mg in association with NNRTIs produced Cmin in the range of those using 300/100 mg without NNRTIs.

The PK of ATV and LPV/r co-administered as part of a double boosted PI regimen in pre-treated patients were studied by two different groups of authors. [10,11] Both studies showed that the combination provided therapeutic plasma concentrations of both PIs, suggesting the lack of drug-drug interactions between ATV and LPV in the presence of low dose RTV.

Finally, Ctrough of ATV and fosamprenavir (FPV) were obtained in 9 patients receiving combination of ATV/FPV/RTV 150/700/100 mg twice-daily (bd) and in 5 patients receiving ATV/FPV/RTV 200/700/100 mg bd at steady state. The results of this analysis indicated that a combination of ATV 150 or 200 mg bd and FPV 700 mg bd with low dose RTV could offer adequate plasma exposures for both drugs. [12]

Interactions between Proton Pump Inhibitors (PPIs) and PIs

The interaction between antacids/PPIs/H2 blockers and PIs continues to attract much interest due to the commonplace usage of these agents in HIV positive agents and the previously reported significant interactions between these classes.

Investigators from Tibotec evaluated the PK of TMC114/RTV when co-administered with 20 mg of omeprazole od or 150 mg bd of ranitidine in healthy volunteers. [13]

After 4 days of either omeprazole or ranitidine the PK of TMC114 was not affected. Therefore, it is unlikely that dose adjustments are necessary when combining these agents. Data on the use of 40 mg of omeprazole was not presented and, although findings may be different in HIV infected subjects, it is helpful for clinicians to have these negative interaction studies performed to allow a degree of reassurance when coprescribing PPIs or H2 blockers and this new compound.

The negative interaction between omeprazole and boosted and unboosted ATV in healthy volunteers was confirmed. [14]

ATV Cmax, AUC, and Cmin for the 400 mg dose were reduced by >93% following the addition of omeprazole. Similarly, when using ATV/RTV 300/100 mg + omeprazole, ATV Cmax and AUC were 50% and 73% lower than historical controls on ATV 400 mg od. In contrast, ATV Cmin increased by 23% relative to the 400 mg dose. However, it should be noted that this remains much lower than concentrations achieved when using regimens in which ATV is boosted. The effect of ATV on omeprazole PK was also investigated. Only a modest increase in omeprazole AUC was observed suggesting that ATV does not appreciably inhibit CYP2C19 in vivo (the enzyme responsible for omeprazole metabolism). The authors concluded that omeprazole and ATV should not be co-administered in the regimens employed in this study.

In contrast, a second study presented at this meeting by Guiard-Schmid et al. investigated ATV Ctrough (samples taken 24 h post dose +/- 4 h) in HIV patients both taking and not taking PPIs. [15]

Of 92 HIV infected individuals, 13 stated they were taking PPIs. Results are summarised in the Table 2.

Table 2 – ATV Ctrough in HIV patients +/- PPIs (samples taken 24 h post dose +/- 4 h): ATV/RTV (300/100 mg)

These results must, however, be tempered with some caution. Firstly, the range of Ctrough are particularly wide (see above), the timing of doses were not observed, and it is possible these results, to quote an eminent pharmacologist “have been caught in the trap of PK variability”. On an individual level, for those patients taking ATV and a PPI, measurement of ATV concentrations would certainly appear prudent.

PK in pregnancy and liver impairment

With more HIV-positive women choosing to have children, and using HAART though pregnancy, understanding the PK/PD of different agents in this group of patients is becoming an increasingly important subject area.

Cassard et al. investigated the PK of LPV/RTV in pregnant women. [16].

Lopinavir (LPV) Ctrough was determined mainly during the third trimester of pregnancy, using a therapeutic range of 3000-7000 ng/mL. Sixteen pregnant HIV-infected women were enrolled; LPV/r doses were 400/100 mg (n=13), 400/200 mg (n=2), and 266/66 mg (n=1), all twice-daily (bd). The median LPV Ctrough was 4011 ng/ml (range <30-9300; n=27). Sixteen LPV Ctrough were in the predefined therapeutic range, 10 were <3000 ng/ml, two <LOQ suggesting adherence difficulties, and one >7000 ng/ml. During pregnancy, three dose adjustments were made according to LPV Ctrough: from 266/66 to 400/100, from 400/100 to 400/200, and from 400/100 to 533/133 mg bd. At delivery, 75% had plasma HIV-RNA <50 copies/mL with the others ranging from 165 to 368 copies/ml. Median CD4 count was 402 cells/mm³ (range 67-700). Overall, the LPV Ctrough reported in this study were lower than those found in non-pregnant women, hence this study confirms the suboptimal LPV Ctrough seen during pregnancy in other studies. [17] The authors suggest that therapeutic drug monitoring in pregnancy could be useful to optimise efficacy of LPV/r containing regimens.

Efavirenz (EFV) plasma concentrations were also investigated in 16 HIV-infected women. Median EFV Cmin was 2253 ng/ml (range <10-12003; n=28) in 12 pregnant women. [18]

No difference between trimesters was observed and 21 EFV Cmin were in the therapeutic range, one >4,000 ng/ml and 3 undetectable (due to adherence problems). In conclusion, 75% of EFV Cmin were within the therapeutic range, suggesting minor or no PK modifications of EFV during pregnancy occurs. Moreover, safety and efficacy were good during pregnancy and at delivery in mothers and newborns. However, it is important to note that efavirenz should only be used in pregnancy when the potential benefit to the mother outweighs the potential risk to the foetus and there are no other appropriate treatment options (see Prescribing Information or Summary of Product Characteristics, 2005).

The impact of co-infection with hepatitis C or hepatitis B on lopinavir/r PK was investigated in HIV patients by authors from Milan, Italy and Liverpool, UK. [19]

Forty one patients were studied, 33 on standard doses of LPV/r, 3 on 533/133 mg and 5 on 266/66 mg bd. 14 were only HIV-positive, 27 were coinfected with HIV and hepatitis B/C, and 7/27 were cirrhotic. The median LPV total and unbound AUC 0-12h were 107150 and 851 ng.h/mL (unbound percentage 0.96%) in the 14 HIV-positive non-co-infected subjects, 92114 and 1073 ng.h/mL (unbound percentage 1.02%) in the 27 co-infected subjects (no statistically significant difference between the two groups was seen), and 87130 and 821 ng.h/mL (unbound percentage 1.11%) in the 7 cirrhotic subjects. In conclusion, LPV total and unbound PK were not affected by hepatitis B/C co-infection. Given the small number of cirrhotic patients, further studies are warranted to characterize LPV pharmacokinetics in this group.

Tipranavir/r 500/200 mg was shown to be safe in subjects with mild hepatic impairment without the need of dose adjustment. However, a 35% increase in TPV AUC was observed in patients with moderate hepatic impairment. Therefore, the influence of moderate hepatic impairment on TPV PK warrants further study and indicates that monitoring of patients with moderately impaired liver function taking TPV/RTV may be required. [20]

Drug interactions with new and existing compounds

The pharmacokinetics of LPV/r 533/133 mg bd were investigated in 18 patients on an NNRTI (5 EFV, 13 NVP) as part of an NRTI-sparing regimens. [21]

Mean (+/-SD) LPV Ctrough was 5435 ± 3157 ng/ml, range 1187-13077. Despite the wide inter subject variability, levels of LPV were therapeutic and stable over 36 weeks.

The pharmacokinetics of nevirapine (NVP) were investigated in 13 patients on 3TC/d4T and NVP 200 mg bd in the presence of a rifampicin-containing regimen. [22]

NVP levels were measured at baseline and following one week of rifampicin treatment. NVP exposure decreased by 46% following the addition of rifampicin. Eight patients had subtherapeutic levels, 7 had the dose increased to 300 mg bd and levels repeated, which showed achievement of therapeutic levels without any short term adverse event. The authors suggested that this may be a strategy when combined with close monitoring of liver enzymes. Further studies with larger sample size are needed.

Twenty patients with TB-HIV diagnosis were also included in a study investigating the drug interaction between rifampicin and saquinavir/ritonavir 400/400 mg bd. [23]

During the study 15 patients dropped out, 14 because of adverse events (mainly hepatic and gastrointestinal). A decrease in SQV and RTV AUC was observed during rifampicin therapy but concentrations were in the therapeutic range. It is important to bear in mind the recent warning in relation to this regimen.

Several drug-drug interactions between new compounds and current available antiretroviral were studied:

TMC125 and ddI [24]

No clinically relevant PK interaction was observed between TMC125, the new NNRTI from Tibotec, (800 mg bd daily) and ddI (400 mg od) in healthy volunteers. TMC125 Cmax, Cmin, and AUC12h were slightly elevated, 16%, 4%, and 11%, during co-administration of ddI compared with TMC125 alone, but this was not considered to be clinically important.

TMC278 and tenofovir [25]

TMC278, the second NNRTI compound in development from Tibotec, caused a 24% increase in tenofovir concentrations. This is not thought to be clinically significant but the clinical studies will need to examine potential increase in kidney toxicity which theoretically could occur. Tenofovir had no effect on the PK of TMC278.

Vicriviroc (SCH417690) and tenofovir [26]

Co-administration of tenofovir with vicriviroc did not affect vicriviroc exposure significantly.

Vicriviroc and AZT/3TC [27]

The combination of vicriviroc 50 mg with AZT/3TC (150/300 mg) was well tolerated and did not result in a significant drug interaction when given to healthy volunteers for 7 days.

Vicriviroc and ritonavir [28]

Administration of various doses of RTV with vicriviroc increased the exposure of vicriviroc by approximately 500% regardless of the ritonavir dose.

Vicriviroc and efavirenz plus ritonavir [29]

Co-administration of vicriviroc with RTV plus efavirenz increased vicriviroc exposure significantly, albeit not as much as with ritonavir alone. Vicrviroc can be given with efavirenz in combination with ritonavir and achieve clinically relevant exposure.Vicriviroc plus ritonavir and lopinavir/r [30]

Co-administration of vicriviroc with lopinavir/r or ritonavir in healthy volunteers resulted in significantly higher exposure to vicriviroc, with similar effects exerted by both combinations.

PK in children

Lopinavir/r PK/PD were assessed in children younger than 24 months and showed rapid viral load decay and increase in CD4 cell counts despite the presence the low LPV plasma levels (lower than those described for other age groups). [31]

Interestingly, a different study investigated the PK of lopinavir/r od in children and showed that despite the wide inter-subject variability, lopinavir/r once-daily regimens can achieve similar Cmin and Cmax to those observed for twice-daily regimens. Significant improvement in CD4 and VL were also observed for lopinavir/r once-daily. [32]

Curras and colleagues measured indinavir plasma concentrations in children on indinavir/r 250/100 mg/m² and showed that 8/13 patients yielded subtherapeutic levels with two patients with undetectable levels. Therefore, even when IDV is boosted by RTV, the high variability observed in the plasma levels suggests that TDM of IDV and dose adjustments are needed. [33]

Source: University of Liverpool drug interactions web site.
http://www.HIV-druginteractions.org

References:

Unless stated otherwise, all references are to the Programme and Abstracts from the 3rd IAS Conference on HIV Pathogenesis and Treatment, Rio de Janiero, July 2005.
http://hivcurecme.aids2012.org/AbstractSearch.aspx

1. Vernazza et al. Viral suppression in CSF and genital tract in ritonavir-boosted “atazanavir only” maintenance therapy (ATARITMO-Study). Abstract WeOa0204.
2. Awni et al. Significantly reduced food effect and pharmacokinetic variability with a novel lopinavir/ritonavir tablet formulation. Abstract WeOa0206.
3. Van Lunzen et al. High rate of virological failure during once daily therapy with tenofovir + didanosine 250mg + efavirenz in antiretroviral naive patients – results of the 12 week interim analysis of the TEDDI trial. Abstract TuPp0306.
4. Agarwala et al. Pharmacokinetic interaction between tenofovir and atazanavir in healthy subjects. Abstract WePe3.3C07.
5. Taburet et al. Pharmacokinetic (PK) parameters of atazanavir (ATV)/ritonavir (RTV) when combined to tenofovir (TDF) in HIV infected patients with multiple treatment failures: a substudy of Puzzle2-ANRS 107 Trial. 10th Conference on Retroviruses and Opportunistic Infections, Boston, USA, February, 2003. Abstract 537.
6. Agarwala et al. Pharmacokinetic interaction between tenofovir and atazanavir coadministered with ritonavir in healthy subjects. 6th International Workshop on Clinical Pharmacology of HIV Therapy, Quebec, Canada, April, 2005. Abstract 16.
7. Louie et al. Factors Increasing the risk of renal dysfunction with tenofovir difumarate (TDF). Abstract TuPe3.5B01.
8. Louie et al. Multidrug resistance protein-2 (MRP2) inhibition by ritonavir increases tenofovir-associated renal epithelial cell cytotoxicity. Abstract WePe3.3C09.
9. Guiard-Schmid et al. Variability of atazanavir plasma concentrations in HIV-infected patients: results of a prospective French cohort. Abstract WePe3.2C13.
10. Azuaje et al. Pharmacokinetics and safety of a double boosting regimen of atazanavir (ATZ), plus lopinavir (LPV), plus minidose ritonavir in multi-drug treated HIV-infected patients. Abstract WePeLB3.2C01.
11. Duvivier et al. Dual boosted atazanavir/lopinavir/ritonavir containing regimen in HIV-1 infected pretreated patients: plasma trough concentration and efficacy results. Abstract WePe3.2C10.
12. Khanlou et al. Interaction between atazanavir and fosAmprenavir in the treatment of HIV-infected patients. Abstract WePe3.3C11.
13. Sekar et al. Pharmacokinetics of TMC114: effect of omeprazole and ranitidine. Abstract WePe3.3C13.
14. Agarwala et al. Pharmacokinetic Interaction between atazanavir and Omeprazole in Healthy Subjects. Abstract WePe3.3C08.
15. Guiard-Schmid et al. Non significant drug interaction between atazanavir and proton pump inhibitors in ritonavir boosted regimen. Abstract WePe3.3C18.
16. Cassard et al. Therapeutic drug monitoring of lopinavir/ritonavir (LPV/r) containing regimen in pregnant HIV-infected women. Abstract WePe3.2C09.
17. Stek et al. Reduced lopinavir exposure during pregnancy: preliminary pharmacokinetic results from PACTG 1026. XV International AIDS Conference, Bangkok, Thailand, July 11-16, 2004. Abstract LbOrB08.
18. Cassard et al. Plasma concentrations of Efavirenz (EFV) in pregnant HIV-infected women treated with EFV containing regimen. Abstract WePe3.2C12.
19. Dickinson et al. The impact of co-infection with hepatitis C or hepatitis B on lopinavir pharmacokinetics in patients infected with HIV. Abstract WePe3.2C06.
20. Cooper et al. The pharmacokinetics (PK) of single-dose and steady-state tipranavir/ritonavir (TPV/r) 500 mg/200 mg in subjects with mild or moderate hepatic impairment. Abstract TuPe3.1B07.
21. Langmann et al. Safety of lopinavir pharmacokinetics in combination with efavirenz or nevirapine in a nuke-free regimen Abstract WePe3.2C08.
22. Ramachandran et al. Increasing nevirapine dose can overcome reduced bioavailability due to rifampicin co-administration. Abstract WePe3.3C02.
23. Cavalcanti Rolla et al. Safety, efficacy and pharmacokinetics of ritonavir 400 mg – saquinavir 400 mg and rifampicin combined therapy in HIV naive patients with tuberculosis. Abstract WePe3.3C03.
24. Scholler et al. No significant interaction between TMC125 and didanosine (ddI) in healthy volunteers. Abstract WePe3.3C16.
25. Hoetelmans et al. Pharmacokinetic interaction between the novel non-nucleoside reverse transcriptase inhibitor (NNRTI) TMC278 and tenofovir disoproxil fumarate (TDF) in healthy volunteers. Abstract WePe3.3C15.
26. Guillaume et al. Pharmacokinetics of SCH 417690 administered alone or in combination with Tenofovir. Abstract TuPe3.1B09.
27. Guillaume et al. The pharmacokinetics of SCH 417690 when administered alone and in combination with lamivudine/zidovudine. Abstract TuPe3.1B03.
28. Seiberling et al. Similar increase in SCH 417690 plasma exposure with coadministration of varying doses of ritonavir in healthy volunteers. Abstract TuPe3.1B06.
29. Saltzman et al. Pharmacokinetics of SCH 417690 administered alone or in combination with ritonavir and efavirenz in healthy volunteers. Abstract TuPe3.1B08
30. Saltzman et al. Pharmacokinetics of SCH 417690 administered alone or in combination with ritonavir or lopinavir/ritonavir. Abstract TuPe3.1B05.
31. Königs C et al. LPV/r (Kaletra) in children younger than 24months – rapid decrease in viral load and stable CD4 counts despite very low plasma levels. Abstract MoPe9.2C10.
    http://hivcurecme.aids2012.org/Abstracts/A2176747.aspx
32. Rosso et al. Pharmacokinetics and 24 week safety and efficacy of lopinavir/ritonavir (LPV/r) BD or QD as part of ART regimen in naive children. Abstract MoPe9.2C21.
33. Curras et al. Therapeutic drug monitoring of indinavir boosted with ritonavir in pediatric patients. Abstract MoPe9.2C02.