NATAP at the  Durban World AIDS Conference 2000
Durban, South Africa, July 9-14

Pharmacokinetic Enhancement: inhibition leads to simplification but at a cost : Reported By Graeme Moyle, MD, Chelsea & Westminster Hospital, London UK

Pharmacokinetic enhancement involves the use of one drug to inhibit the metabolism of another, leading to improved drug exposure. The most popular candidate for this approach is ritonavir, which is a potent inhibitor of cytochrome (CYP) p450 3A, the liver and gut wall cytochrome responsible for metabolism of many drugs including other protease inhibitors (PI). Ritonavir increases exposure and slows the metabolism of other protease inhibitors leading to potential for using fewer tablets and having less frequent dosing. It also removes the need for food restrictions and at least with saquinavir the need to separate dosing from buffered ddI. Furthermore, the interpatient variability in exposure with PIs is diminished when ritonavir co-dosing is used. Ritonavir is also known to inhibit p-glycoprotein, a cellular efflux pump. Inhibition of this pump may lead to increased cellular concentrations of other PIs and improved penetration into body compartment such as the brain. However, there are potential downsides to the use of ritonavir. It is known (as with other PIs) to increase (mostly) LDL cholesterol and triglycrides in what is probably a dose dependent manner. Inhibition of CYP3A may lead to interactions with other drugs the patient is prescribed or with illegal substances (such as ecstasy). Additionally, the long-term consequences, if any, of chronically inhibiting CYP3A and P-glycoprotein is not known.

Whist the first studies if ritonavir enhancement were conducted with saquinavir, use of small or ëbabyí doses (usually 100-200mg/day) of ritonavir with other PIs is increasingly standard practice and a co-formulation of 100mg bid with lopinavir (ABT-378) is currently in advanced development. Until this meeting, much of the available data on use of ritonavir with indinavir, amprenavir or nelfinavir was derived from either small pharmacokinetic studies or observational cohorts rather than prospective studies.

Two prospective studies presented today evaluated combining ritonavir and indinavir in subjects established on tid dosed indinavir and with viral loads <400 copies/ml. The studies differed in the dosing. Combining 400mg of each drug bid may mean that therapeutic levels of both ritonavir and indinavir are achieved, potentially giving a dual PI potency and is associated lower indinavir peak levels, potentially diminishing the risk of renal calculi and crystalluria from indinavir. Using 100mg of ritonavir with 800mg indinavir bid is cheaper, uses fewer pills (3 bid versus 5 bid with 400/400) and has a lower risk of ritonavir related side effects such as lipid disturbances, nausea or diarrhoea.

The NICE study evaluated patients with HIV RNA <400 copies/mL in an open-label multicenter study comparing continuing indinavir 800mg tid to switching to 400/400mg bid of ritonavir/indinavir. A survey addressing adherence and convenience, was administered at the baseline and week 4 was the basis of the presentation. Efficacy data were not presented. The study has recruited 380 patients, 301 randomised to add ritonavir and 79 to remain on tid indinavir. After just 4 weeks 21% of those adding ritonavir and 15% remaining on indinavir alone have discontinued. Adverse events, mainly gastrointestinal, were the cause of discontinuation in 14% and 8% of patients, respectively. The adherence survey at week 4 visit indicated that patients randomized to add ritonavir were missing fewer doses than they had reported missing prior to initiation of this regimen (p>.001). Additionally, they reported that it was easier to take the medication as prescribed, easier to take at the same time each day, and easier to coordinate with meals when compared to baseline  (p>.001 in each case). Similar effects were not seen for patients who remained on indinavir alone. Thus, there seems to be a trade off with adding this dose of ritonavir between improved administration characteristics versus a modest increase in risk of toxicity.

A second study, this one called BEST, found a similar trade off existed with modifying dosing of indinavir to 800mg bid with 100mg of ritonavir (originally using RTV liquid formulation). This randomized, open-label, multicenter study testing whether switching in 326 patients with viral loads <500 copies/ml. 161 added ritonavir, 165 remained on indinavir alone.

All patients completed 3 months follow-up with 237 patients through week 24. Baseline characteristics of both groups were similar with CD4 counts of 407 and 440/mm³ for tid and bid arms, respectively. Proportions of patients with plasma viral load <500 copies/ml at 6 months are:

Adverse events requiring treatment interruption or discontinuation occurred in 7 (TDV TID) versus 19% of patients (RTV/IDV 100/800 bid), mostly due to GI intolerance. The RTV liquid form could have caused GI intolerance. Nephrolithiasis developed in 5% versus 12% (IDV/RTV 800/100) leading to treatment discontinuation in 2% versus 3%, respectively. The high rate of nephrolithiasis over a relatively short period of follow is disappointing and underlines the need for continued high fluid intake on this dosing schedule. Additional adverse events included nausea and/or vomiting which occurred in 2 versus 16% of patients, possible in part due to the use of liquid ritonavir during the first months of the study. No differences in triglycerides or cholesterol >3 times upper limit of normal were observed [2].

Other PIs evaluated with ritonavir in pharmacokinetic studies were amprenavir and nelfinavir.

In evaluating the PK interaction between Ritonavir  and amprenavir three RTV-APV regimens were tested in 12 healthy volunteers per group: Group I 400mg Ritonavir + 450mg Amprenavir, group II 400/750 and group III 200/1200. Withdrawals, in all 19 cases  due to amprenavir rash (despite excluding persons with known sulpha drug allergy) meant only seventeen subjects finished the 12-day study. Pharmacokinetic parameters were compared with historical controls taking the approved 1200mg bid dose. PK parameters are shown in table.

Group. III had significantly higher mean amprenavir exposure than those of Groups I and II, but an elimination half-life 50% shorter. These data suggest ritonavir improves the PK profile of amprenavir with all three regimens yielding trough values at 12 hours above current recommended amprenavir dosing (3).

With nelfinavir, the possiblity of once daily dosing with ritonavir was explored. Nelfinavir is not only matabolisd by CYP3A but also by CYP2C19, an enzyme not significantly inhibited by ritonavir. As a result, only a modest enhancement of 17-49% in nelfinavir (plus M8 its active metabolite) exposure is achieved. A range of doses were evaluated. A dose of 200mg ritonavir and 2500mg nelfinavir produced a higher AUC and similar trough concentration of NFV (and a slightly higher nelfinavir + M8 exposure) to standard 1250mg bid dosing. Subjects receiving 100mg of ritonavir did not achieve comparable trough values to standard dosing. These data suggest the feasibility for dosing nelfinavir plus ritonavir once daily (4) and warrant further clinical evaluation. Whilst with the current formulation the tablet load on the single occasion would be quite high (12 pills: 2 ritonavir plus 10 nelfinavir), however, a new formulation of nelfinavir as 625mg tablets could mean once daily PI therapy could be achieved with just six tablets

DeJesus E, Pistole M, Fetchick R, et al. A randomized, controlled, open-label study comparing the adherence and convenience of continuing Indinavir Q8H vs Switching to norvir/indinavir 400 mg/400 mg BID (The NICE Study). XIII International AIDS Conference, Durban, July 9-14, 2000: abstractWeOrB482

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

Hsu A, Williams L, Chiu Y-L, et al. Pharmacokinetic (PK) interactions between ritonavir (RTV) and amprenavir (APV) in healthy volunteers. XIII International AIDS Conference, Durban, July 9-14, 2000: abstract WeOrB546

Hsyu PH, Lweis RH, Tran JQ, et al. Pharmacokinetics (PK) of nelfinavir (NFV) after once daily dosing in in combination with mini-doses of ritonavir (RTV) in healthy subjects. XIII International AIDS Conference, Durban, July 9-14, 2000: abstract LbPeB7049.