Presentations

Clinical optimisation of protease inhibitor pharmacokinetics

Abstract

Clinical pharmacology is rapidly emerging as a major issue for optimal HIV management, as exemplified by the observation that knowing the resistance profile of a drug without knowing its plasma level can be likened to having viral load data in the absence of a CD4 count. Despite proven efficacy of protease inhibitor (PI)-based therapy, the pharmacological profiles of some PI drugs can complicate therapy in several ways: a short half-life (T1/2) may necessitate frequent and inconvenient dosing; rapid clearance requires the use of high doses and the subsequent high plasma peak (Cmax) levels can reduce the tolerability of the regimen; low plasma trough (Cmin) levels can lead to an intermittent loss of viral suppression that promotes the evolution of drug resistance. The use of a dual-PI regimen in which pharmacokinetic interactions between the two drugs raise Cmin may strengthen the regimen by preventing the emergence of drug resistance. Supporting evidence for this conjecture can be found in the demonstrated association between PI Cmin and both the rate of development of resistance mutations [1] and the extent of virological suppression over time. Interpatient variability in PI metabolism and therefore drug exposure � itself associated with in vivo virological response [2] � is another factor that may respond favourably to the use of a dual-PI regimen with improved pharmacokinetics. Thus, pharmacokinetic (PK) boosting should result in enhanced antiviral potency � including potency against drug-resistant strains � while simultaneously reducing the pill burden, dosing schedules, and possibly cost.

Mechanisms of PK boosting
The co-administration of small doses of ritonavir (RTV) significantly improves the pharmacokinetics of other PIs. The potent inhibitory action of RTV on cytochrome P450 (CYP) 3A4 in the gut reduces first-pass PI metabolism and so prolongs Cmax, while inhibition of CYP 3A4 in the liver reduces systemic drug metabolism and so prolongs T1/2. RTV boosting, however, does not follow the same pattern for all PI drugs. For saquinavir (SQV) and lopinavir (ABT-378), the predominant effect of RTV is to elevate Cmax, while for indinavir (IDV), nelfinavir and amprenavir, RTV boosting primarily extends T1/2 [3,4]. In the case of nelfinavir, boosting with RTV results in a substantial increase in the plasma levels of its active metabolite, M8, and this may prove to be of clinical relevance, therefore warranting further investigation [5]. Saquinavir is one of the most widely studied of the PIs with respect to RTV boosting, and its in vivo Cmax and Cmin under boosting are in good agreement with predicted estimates across a wide range of SQV dosages. The ratio of observed SQV Cmin to the in vivo 95% inhibitory concentration (EC 95) for HIV replication is high for all twice-daily (bid) SQV/RTV combinations studied. However, it should be stressed that while Cmin /EC ratios are often used as a predictor of antiviral potency for RTV-boosted regimens, the procedures for determining its components are not standardized and estimates of the ratio will vary considerably depending on how each factor is assessed [6]. Hence, the only effective means of evaluating a boosted regimen is by direct, head-to-head clinical trials.

Regardless of how it is evaluated, the goals of any boosted regimen are the same: to improve PI pharmacokinetics in terms of potency, durability and activity against drug-resistant virus; to reduce pill burden and frequency of dosing; to reduce or abolish dietary or other restrictions; and to improve regimen tolerability and cut the cost of therapy by reducing the amount of PI to be taken.

Twice-daily dosing
A bid regimen of 400 mg SQV plus 400 mg RTV is already well-established in HIV therapy [7,8]. More recent data on the development of bid dosing of IDV/RTV combinations from the Protocol 078 study show improved 12-hour pharmacokinetics for 800 mg IDV plus 100 mg RTV bid. However, increased hydration is required while on IDV/RTV to offset the well-known nephrolithiasis associated with the use of IDV. Clinical data from the bid Efficacy and Safety Trial (BEST) for RTV-boosted bid IDV compared with unboosted three-times-daily (tid) IDV showed similar overall efficacy, but incidence of kidney stones was higher on the boosted regimen (10% versus 4%) [9].

Once-daily (qd) dosing
The possibility of qd dosing for RTV-boosted SQV and IDV is currently under investigation, and Fortovase � (FTV; SQV soft gel capsules) has shown early promise as a qd agent [10]. The addition of 100 mg RTV to 1600 mg FTV given once daily yields an enhanced 24 hour pharmacokinetic profile that is unaffected by the administration of the nucleoside analogue ddI in healthy volunteers. The mean 24- hour Cmin for this combination is well above the EC 95, and the 24-hour area under the FTV concentration- time curve (the AUC 24) is 300-700% greater than in the absence of RTV (see figure 1).

Figure 1

Figure 2

IDV has also been studied as a qd alternative in normal volunteers. The most effective combination studied (IDV 800 mg/RTV 200 mg qd) showed a higher Cmax (9.1 versus 6.7 �g/ml) than the 800/100 bid regimen, which explains the increase in adverse events noted. In particular, this is expected to further increase the higher rate of kidney stones seen previously in the BEST study with the 800/100 regimen.

In summary, based on these data, our centre currently recommends the use of RTV-boosted PI regimens, specifically Fortovase� and indinavir based bid therapy as well as qd SQV 1600/1200 mg with 100 mg RTV.

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References

1. Molla A, Korneyeva M, Gao Q et al. Ordered accumulation of mutations in HIV protease confers resistance to ritonavir. Nature Medicine 1996; 2:760-766

2. Gieschke R, Fotteler B, Buss N and Steimer JL. Relationships between exposure to saquinavir monotherapy and antiviral response in HIV-positive patients. Clinical Pharmacokinetics 1999; 37:75-86

3. Kempf DJ, Marsh KC, Kumar G et al. Pharmacokinetic enhancement of inhibitors of the human immunodeficiency virus protease by co-administration with ritonavir. Antimicrobial Agents and Chemotherapy 1997; 41:654-660

4. Hsu A, Granneman GR, Cao G et al. Pharmacokinetic interaction between ritonavir and indinavir in healthy volunteers. Antimicrobial Agents and Chemotherapy 1998; 42:2784-2791

5. Kurowski M, Kaeser B, Mroziekiewicz A et al. The influence of low doses of ritonavir on the pharmacokinetics of nelfinavir 1250 mg bid. 40th Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, Canada, 17-20 September 2000.

6. Hill A, Craig C and Whittaker L. Prediction of drug potency from Cmin /IC 50 or Cmin /IC 95 ratio: false precision? Antiviral Therapy 2000; 5 (Suppl. 3):50-51

7. Kirk O, Katzenstein TL, Gerstoft J et al. Combination therapy containing ritonavir plus saquinavir has superior short-term antiretroviral efficacy: a randomized trial. AIDS 1999;13:F9-16

8. Department of Health and Human Services and Henry J Kaiser Family Foundation. Guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents. Available at: http://hivatis.org January 28 2000

9. Gatell JM, Lange J, Arnaiz JA et al. A randomized study comparing continued indinavir (800 mg tid) to indinavir/ritonavir (800/100 mg bid) in HIV patients having achieved viral load with indinavir plus 2 nucleoside analogues. The bid efficacy and safety trial (BEST). The XIII International AIDS Conference, Durban, South Africa, 9-14 July 2000. Abstract WeOrB484

10. Saag MS, Kilby M, Ehrensing E et al. Saquinavir systemic exposure and safety of once-daily administration of Fortovase � (saquinavir) soft-gel capsule (FTV) in combination with low-dose ritonavir (RTV). 39th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, California, USA, 26-29 September 1999. Abstract 330

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Biography

Dr Montaner received his MD with Honors in 1979 at the University of Buenos Aires, Argentina. In 1981, he joined the University of British Columbia as a post-doctoral fellow. He then completed a residency in Internal Medicine and Respiratory Medicine at UBC. He was Chief Resident for the Department of Medicine in 1986/1987.

In 1988 Dr Montaner joined the Faculty at St. Paul�s Hospital/University of British Columbia as the Director of the AIDS Research Program and the Infectious Disease Clinic. He is the Director, Clinical Activities of the BC Centre for Excellence in HIV/AIDS and a founding co-Director of the Canadian HIV Trials Network. He held a National Health Research Scholar of Health Canada (NHRDP) for a period of 10 years starting in 1988. In 1996 he successfully competed for the Endowed Chair on AIDS at SPH/UBC. In 1997, he was appointed Professor of Medicine at UBC.

Dr Montaner has published extensively with regard to respiratory complications of AIDS and antiretroviral therapy for HIV infection. Of note, he pioneered the use of adjunctive corticosteroids for AIDS-related Pneumocystis carinii pneumonia. Later on, his work played a significant role in establishing the relationship between the development of HIV resistance to nucleoside analogues and clinical progression of the disease. Over the last couple of years, Dr Montaner was involved in several important international studies including the AVANTI Trials, CAESAR and INCAS. Also, he evaluated several alternative therapeutic approaches, such as Acemannan, Hydroxyurea and GP160. More recently, Dr Montaner has focussed on simplification of antiretroviral therapy and the management of multiple drug resistant HIV. He has also initiated a new effort to characterize the long term safety of antiretroviral therapies.

Dr Montaner is the Editor of the BC Centre Therapeutic Guidelines. Also, he is responsible for several aspects of the Drug Distribution Program for the BC Centre for Excellence in HIV/AIDS.

Dr Montaner is a member of the Scientific Committees for the bi-annual International Conference on HIV Therapy. He is the co-chair of the Annual International Workshop on Salvage Therapy. He was the co-Chair of the Scientific Program and a member of the Organizing Committee for the XIth International Conference on AIDS, which attracted 15,000 participants to Vancouver in the summer of 1996. He is the Track B co-Chair for the 2001 IAS Conference on AIDS Therapeutics. He is a member of the International AIDS Society (USA) Expert Panel on Antiretroviral Therapies. He is the Treasurer of the Canadian Association for HIV Research and an elected member of the Council of the International AIDS Society.

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