Once Daily Protease Regimens: SQV+RTV, IDV+RTV, APV+RTV, 423+IDV, BMS-232632. Twice Daily Double PI Salvage Therapy: IDV+RTVand RTV+APV

One of the concerns related to the IDV dosing used in these studies is the potential for developing higher incidence of kidney stones. Another concern raised about once daily PI dosing is the effect of missing doses in the once-daily regimens. But, once daily regimens may be particularly useful for directly observed therapy. Initial pharmacokinetics data from studies in healthy volunteers for three once daily protease inhibitor regimens were reported at ICAAC.

RTV+APV. A once a day regimen of amprenavir (APV) and ritonavir is being explored. GW is planning to study 1200 or 900 mg once daily amprenavir with 200 or 300 mg once daily ritonavir. This concept emerged from a study of amprenavir +efavirenz+ ritonavir or nelfinavir.  Previously it had been shown that efavirenz could significantly reduce amprenavir blood levels. But GW has reported that adding 200 mg BID ritonavir appreciably increases amprenavir blood levels and these increases are sustained even when adding efavirenz. So not only does adding RTV to APV increase APV blood levels (AUC & Cmin but not Cmax), but those same increased levels are sustained even after adding EFV. A higher dose of 500 mg BID ritonavir did not appear to be any more beneficial than the 200 mg BID RTV dose. GW also found that 1250 mg BID nelfinavir had the same effect as 200 mg RTV BID but there appeared to be additional diarrhea. A clinical study of APV+RTV+EFV (1200 bid/200 bid/600 qd) in a salvage situation is ongoing and the data will be reported.

Merck is developing a new protease inhibitor (423) that will be used in combination with IDV because IDV raises its blood levels. Several dosing regimens are being explored in a human study.

Al Saah from Merck reported pharmacokinetics (drug blood levels) data from a preliminary study in 37 healthy volunteers comparing indinavir 800 mg every 8 hours to three IDV/RTV once daily regimens: 800/100, 800/200, and 1200/100. IDV was taken without regard to food in the 3 non-standard dosing regimen. Historical data was used from the standard fasting 800 every 8 hrs. Merck is planning to explore 1200/200 in a clinical study to improve the IDV Cmin by increasing the RTV dose from 100 to 200 mg once daily. The 1200/100 dose had significantly increased Cmax and AUC-24h compared to the standard IDV dose of 800 mg every 8 hrs. (See Table 16):  

Table 16.


Cmax (uM)

AUC-24h (uM.h)

Cmin-24 (nM)

800/100 (IDV/RTV)


79.8 (range- 71.5, 89)

164 (142, 189)



99.6 (88.2, 112.4)

189 (118, 304)



130.3 (108.8, 156.1)

273 (233,320)

IDV 800 every 8 hrs


83.4 (66.6, 104.6)

211 (163,274)

It remains uncertain if the higher Cmax and AUC may lead to increased incidence of kidney stones. The planned clinical study will hopefully answer that question. Saah reported that 3 volunteers discontinued for the following adverse events: 1/11 discontinued from the 1200/100 arm due to numbness of the face and tongue; two discontinued from the 800/200 arm, 1 due to numbness of the face and tongue and decrease in skin sensation and the other due to vomiting. One person was lost to follow-up.

D Burger also reported pharmacokinetics data from a preliminary study of 12 healthy volunteers using IDV/RTV 1200/200 and 1200/400 once daily. The optimal dose regimen was selected based on 4 criteria: IDV Cmin above 150 nM, a minimum number of samples with IDV concentrations above 16,000 nM, absence of serious adverse events (grade 3 or 4), and subjective adverse events score. In the 1200/200 dose group 1/5 patients had median Cmin >150 nM, while 3/6 patients had median Cmin >150 nM in the 1200/400 dose group. 5/10 patients in the 1200/200 group had concentrations >16,000 nM while 6/21 achieved that in the 1200/400 group. But the patients reported 2.9 subjective AEs in the 1200/400 group and 0.7 in the 1200/200 group. In the 1200/200 group the median AUC-24h was 110,260 nM.hr, the Cmax was 17,264 nM and the Cmin was 81 nM. In the 1200/400 group the median AUC-24h was 136,971, Cmax was 18,241, and the Cmin was 147. No serious adverse events were reported (grade 3 or4). Ritonavir inhibited indinavir clearance by 51-70% leading to increased and prolonged exposure of indinavir.

Burger reported on two HIV-infected individuals who were not able to adhere to their previous regimens, and started to use 1200/400 once daily  (+2 NRTIs) outside the study. Burger reported the 2 tolerated this regimen during 2 and 4 months, respectively. Remarkably, the RTV levels were above the minimum effective concentration of 2.1 mg/L during about 75% of the dose interval. Burger said the relevance of having therapeutic levels of both IDV and RTV is unknown. Both of these two patients had higher AUC, Cmax and Cmin compared to the study individuals median values-- patient 1- 201,954 nM.hr AUC; 21,336 Cmax and Cmin of 1,352 nM (compared to 147 nM in the 1200/400 group. Patient 2- 161,564 nm.hr AUC, 22,801 nM Cmax, and 521 nm Cmin. So, the data preliminarily suggests that 1200/400 results in higher Cmin but in the study patients reported a higher incidence of subjective adverse events.

Burger concluded the optimal dose is 1200/200 but added an initial dose of 1200/400 may be necessary to assure adequate trough levels of Idv from day 1. He recommended that steady state PK of QD IDV/RTV regimens should be studied in HIV-infected humans.

IDV/RTV BID.  William O'Brien reported data from a study using 800/100 and 800/200 IDV/RTV BID with food for salvage for individuals with prior treatment experience. Subjects also received 2 or 3 NRTIs. The baseline viral load was high at 286,000 copies/ml, and CD4s were 196.  Subjects had 15 months prior protease inhibitor use and 34 months NRTI use. Other studies using RTV+IDV for salvage have shown effectiveness for individuals who’ve previously failed PIs. Mike Youle reported IDV+RTV+EFV+HU+ddI+NRTIs was effective. Cassy Workman has reported RTV+IDV may be effective against PI resistant virus.

Results: Five of 16 reduced their viral load to <50 copies/ml. An additional 4 of 16 reduced viral load by 1 log or more. There may be a diminshed response by patients harboring the L90M mutation: none of the 5 responders had this mutation at baseline; 3/4 partial responders (>1 log reduced VL) had the L90M; and, 6/7 non-responders had the L90M at baseline. O'Brien reported 6 cases of kidney stones and 3/6 required discontinuation. But he said the study was initiated just prior to one of the hottest summers in the history of South Texas, perhaps accounting for the very high incidence of kidney stones. O'Brien reported 800/200 gives higher, more consistent indinavir trough and peak levels than 800/100, the combination should be taken with food, patients need to be encouraged to maintain good hydration to avoid kidney stones.

However, clinical advantage among these 3 dosing regimens, 400/400, 800/100 and 800/200, has yet to be established.

Once Daily SQV with Low-dose RTV. Mike Saag of the University of Alabama-Birmingham reported preliminary pharmacokinetics data from a study of once daily (QD) Fortovase in combination with low dose ritonavir. Forty-one healthy volunteers completed an open-label, randomized study of either FTV alone (TID) or FTV with ritonavir. Subjects received one of six regimens; there were 8 or 9 people in each arm (See Table 17):  

Table 17.


Cmax (ug/mL)

Cmin (ug/mL)

AUC-24h (ugh./mL)

1200 FTV TID alone




1200/100 FTV/RTV QD




















Although there was no clear dose proportional increase in SQV exposure the 1600/100 had the highest AUC-24h. Saag reported that 1600/100 has been selected as the dose for further evaluation. 

BMS-232632. This is a new once a day PI being made by Bristol Myers. Early in vitro data show to be active against PI resistant HIV, and HIV with PI resistance appears to be sensitive to BMS-232632. This is preliminary data that will have to be confirmed with human studies. Initial human studies are ongoing.