Highlights from the First International Workshop on Clinical Pharmacology of HIV Therapy, Noordwijk, The Netherlands, March 30-31, 2000.
- Using efavirenz with bid IDV/RTV 800/100mg
- ABT-378/r with other PIs
- Amprenavir and ritonavir
- Amprenavir/ritonavir and efavirenz
- Saquinavir food guidelines
- Once daily IDV/RTV
- References
Using efavirenz with bid IDV/RTV 800/100mg: Eighteen healthy volunteers received IDV/RTV for 14 days before assessment of IDV/RTV steady state on day 15. EFV was added for a further 14 days and drug concentration tests were repeated at day 29. EFV levels were unaffected, and IDV levels remained above the therapeutic threshold (0.10mg/L) in all cases despite a 48% decline in Cmin and total exposure (-19%). No dosage adjustment recommended (Aarnoutse).
ABT-378/r with other PIs: The favourable pharmacokinetic profile of ABT-378/r may make it an attractive drug to combine with other protease inhibitors for individuals with high level resistance to at least one PI, on the grounds that any reduction in sensitivity will be offset by the enormously high therapeutic index of ABT-378 (Hsu).
Abbott Laboratories reported on the effects of ABT-378/r on other blood levels of other protease inhibitors. Individuals received 10 days treatment with ABT-378/r 400/100mg before receiving a single 800mg dose of saquinavir and a single dose of indinavir (600mg) the following day. Another group received a single 750mg dose of nelfinavir instead. In a second study, individuals received ABT-378/r for 17 days before receiving either 500mg or 750mg of amprenavir bid for five days. Pharmacokinetic measures were compared with historical data.
In all cases the trough levels of the concomitant PI were increased. The most pronounced increase was seen with saquinavir, where the trough level increased fourfold. In contrast the Cmax level increased by just 30%, implying that any increase in side effects could be small.
In the cases of the single dose of indinavir, total exposure was reduced compared with 800mg three times daily, but the trough level was twice as high as that seen with indinavir alone. Amprenavir perfomed similarly to indinavir, with a clear indication that the amprenavir dose should be reduced to 750mg rather than 500mg to ensure a greater improvement in trough levels.
In summary, suggested PI doses when combined with ABT-378 are:
- Indinavir: 600mg bid
- Saquinavir: 800mg bid
- Amprenavir: 750mg bid
- Nelfinavir: 750mg bid
Amprenavir and ritonavir: The use of amprenavir as a salvage therapy in individuals who have experienced multiple PI failures is still under investigation. As with ABT-378, BMS-232 and tipranavir, methods of boosting amprenavir levels to overcome reduced drug sensitivity are being investigated.
Combining amprenavir with ritonavir has been proposed in order to increase plasma exposure. Using pharmacokinetic data from PRO10017 and PRO10022 together with previous data on ritonavir, investigators from Glaxo-Wellcome US took clinical isolates from individuals who had failed amprenavir or multiple other PIs and calculated whether ritonavir could be expected to boost amprenavir levels sufficiently to control viral replication.
In the case of first-time amprenavir failures, they estimated that 100mg ritonavir could be expected to increase APV levels to 3.2 times the level needed to suppress viral replication (range 0.7-152.4), whilst in the case of multiple PI failures, ritonavir could be expected to increase APV levels by 2.2 times (range 0.6 - 24.3 times). The authors suggest that an APV/RTV 600/100mg regimen may be effective in individuals with multiple-PI failure (Stein).
Amprenavir/ritonavir and efavirenz: Efavirenz has been shown to reduce blood levels of amprenavir substantially, making it problematic to combine the two drugs for individuals who may have reduced sensitivity to amprenavir due to prior PI failure.
A retrospective analysis of patients at the Claude-Bernard Hospital in Paris shows that APV/RTV 450/100mg combined with efavirenz has a Cmin comparable to that of amprenavir/ritonavir alone, suggesting that a small dose of ritonavir offsets any negative effects of efavirenz on amprenavir levels.
This regimen would also reduce the pill burden and hence the cost of the amprenavir-containing regimen, from eight pills to three twice daily (Lamotte).
A second study, using 200mg of ritonavir instead of 100mg, was conducted in Germany, and confirmed these observations in eight patients, three of whom reported mild adverse events (Degen).
Saquinavir food guidelines: Soft-gel saquinavir capsules are currently recommended to be taken with food, but some patients are confused about exactly what sort of food they need to eat in order to maintain adequate levels of saquinavir. A team from the Netherlands discovered that some patients receiving saquinavir-sgc had lower than expected plsma saquinavir levels, and set out to investigate the effects of fat, grapefruit juice and ritonavir on saquinavir levels.
On the first day 6 patients were given a `normal' breakfast and 1200mg of saquinavir at the hospital and had their blood levels measured over an eight hour period. The following day the patients received a breakfast much higher in fat (54% vs 33%, 1040 kcal vs 600kcal).
Even the meal described as one of normal fat content may appear high in fat and carbohydrates to some people, especially for breakfast time. It's the equivalent of a plate of bacon and eggs or two Mars bars.
After the high fat breakfast, blood levels were increased substantially when compared with the `normal' breakfast.
Two of the individuals also underwent additional tests. In one case, a patient received a normal breakfast with grapefruit juice, and in the other case a patient received SQV/RTV 400/400mg with a normal breakfast. With grapefruit juice plasma exposure was greater than with a high fat breakfast, and ritonavir also improved saquinavir exposure substantially.
Even if TDM becomes routine in cases of therapeutic failure, it would appear that accurate and repeated information about drug and food interactions will continue to be essential (Hugen).
Once daily IDV/RTV: A Spanish group reported the first data on the use of a once-daily indinavir/ritonavir combination in HIV-infected individuals. Two studies in HIV-negative volunteers have previously suggested that the combination produces similar trough levels to those seen with three times daily indinavir.
In this study 27 treatment-naive individuals received IDV/RTV 800/200mg plus AZT/3TC (as Combivir) for the first four weeks. Eight out of 27 stopped therapy within the first four weeks due to side effects described as ritonavir-related. In this study the liquid formulation of ritonavir was being used, which may explain the high drop out rate.
After four weeks drug levels were tested and dosages were adjusted to 1000/100mg once daily (n=9) or 800/100mg once daily (n=7). Nine individuals eventually reduced their indinavir dosage from 1000mg to 800mg.
After 32 weeks 15/16 of the remaining patients had viral load below 5 copies and indinavir Cmin above the minimum therapeutic trough level (if the Cmin of 0.10mcg/mL is generalisable for all patients). However, the range of once daily Cmins in the once daily group was substantially lower than in the twice daily group, suggesting much less forgiveness if doses are missed (Mallolas).
Aarnouste R et al. A pharmacokinetic (PK) study to investigate the influence of efavirenz (EFV) on a bid indinavir/ritonavir regimen (800/100mg) in healthy volunteers. First International Workshop on Clinical Pharmacology of HIV therapy, Noordwijk, abstract 2.3, 2000.
Degen O et al. Steady state plasma pharmacokinetics of amprenavir (APV) 450mg bid and ritonavir (RTV) 200mg bid with or without efavirenz (EFV) in HIV-1 infected individuals. First International Workshop on Clinical Pharmacology of HIV therapy, Noordwijk, abstract 2.7, 2000.
Hsu A et al. Interaction of ABT-378/ritonavir with protease inhibitors in healthy volunteers. First International Workshop on Clinical Pharmacology of HIV therapy, Noordwijk, abstract 2.4, 2000.
Hugen P et al. Differences in pharmacokinetics (PK) of saquinavir soft-gel capsules after a normal and high fat breakfast. First International Workshop on Clinical Pharmacology of HIV therapy, Noordwijk, abstract 7.3, 2000.
Lamotte C et al. Amprenavir (APV) plasma concentrations are dramatically increased by association to ritonavir (RTV) baby doses in HIV-infected patients: possible combination with efavirenz. First International Workshop on Clinical Pharmacology of HIV therapy, Noordwijk, abstract 2.7, 2000.
Mallolas J et al. A dose finding study of once-daily indinavir/ritonavir plus Combivir in HIV-infected patients. First International Workshop on Clinical Pharmacology of HIV therapy, Noordwijk, abstract 2.14, 2000.
Stein D et al. Pharmacodynamic effects of amprenavir (APV) + ritonavir (RTV) on different viral populations. First International Workshop on Clinical Pharmacology of HIV therapy, Noordwijk, abstract 5.2, 2000.