Drug interactions: amprenavir, saquinavir, ABT-378/r (lopinavir/r), indinavir, efavirenz, ritonavir

15 May 2000. Related: Conference reports, PK and drug interactions, PK Workshop 1st 2000.

Simon Collins, HIV i-Base

Fourteen of the presentations reported on specific drug interactions, some of which had been reported at earlier meetings.

Interactions between St John Wort and antiretrovirals have received extensive publicity recently (see HTB no.1), which were further strengthened by a new study at this meeting, showing that nevirapine levels were reduced by 19% when co-administered with hypericum [1].

Other studies though were also new to this meeting. In fact, learning of new interactions between anti-retrovirals that are already widely available and already being used together in combinations, emphasised the practical importance of being able to confirm dosing by measuring drug levels that are actually achieved. This is especially important in the context of multi-drug (often mega-drug) combinations that are providing optimistic results for patients in salvage therapy. Triple-PI, dual-NNRTI and multiple PI/NNRTI combinations are already being reported, and it in not possible or realistic for every combination to be studied in a trial setting before use.

The take home message from all these studies is that TDM should play a key role whenever considering combinations of drugs for which there is no clear interaction data. As many of these unknown interactions will come from the new of compounds in salvage studies and expanded access programmes, this will only be possible if manufacturers work together with independent laboratories to enable drug-level assays to be produced for use in expanded access programmes.

Availability of pure compound to enable labs to produce these assays prior to availability in expanded access became one of the more political requests made to the pharmaceutical companies present from both pharmacologists, clinicians and activists present.

Baby-dose ritonavir improves amprenavir profile

Although not approved by the EMEA at its first application for licensing, amprenavir may in fact offer advantages over other PIs if it is shown to provide a distinct resistance and side-effect profile. As with some other PIs though, it’s optimal use is likely to be when co-administered with ritonavir, which leads to a reduced pill count and improved PK profile. This was supported in a study by Lamotte and colleagues from X.Bichat-C.Bernard Hospital Paris, which showed wide inter-patient variability in Cmin of amprenavir when used alone. This boost provided sufficient to enable efavirenz to be used concomitantly with APV/RTV. Efavirenz reduces levels of APV AUC by around 36% and the two drugs should otherwise not be used together. As shown in Table 6, co-administration of these BD regimens resulted in APV Cmin at least 10-fold higher than when APV was used alone. Inter-patient variability was also wide. [1]

Data was not provided on Cmax or AUC levels but a Glaxo-Wellcome study in HIV-negative subjects presented at the 7th Retrovirus Conference showed that RTV (300mg BD) increased AMP (450mg BD) Cmax by 9%, Cavg by 238% and Cmin by 1325% and pointed to further studies within QD regimen. [3]

Ritonavir and indinavir with efavirenz

Aarnoutse and colleagues showed indinavir Cmin reduced by -48% and AUC by -19%, in 18 HIV-negative volunteers (at steady state with bid IDV/RTV 800/100) following 14 days of concomitant efavirenz (600mg QD). No dosage adjustment was recommended. [4]

Interaction of ABT-378/r (lopinavir/LPV) with PIs

Now available in the UK through both named-patient and the open label safety evaluation programmes, there will undoubtedly be a group of patients who look to LPV with other PIs in a salvage context. Ann Hsu presented results of a PK study where single doses of saquinavir, indinavir and nelfinavir to HIV-negative volunteers induced following 10 days 400/100 BID lopinavir. A second study added amprenavir/ritonavir (450/100,750/100 BID) for 5 days to steady state (17day) LPV.

Table 1: Summary of APV Cmin (target 100ng/ml)able 2: PK results were with lopinavir (L) and compared to historical data

Table 2: PK results were with lopinavir (L) and compared to historical data

Dosing recommendations with lopinavir (400/100 BD) from this study were:

• SQV 800mg BD
• IDV 600mg BD
• APV 750mg BD
• NFV 750mg BD

Although at the above doses, nelfinavir had the most significant effect by reducing lopinavir AUC by 23% and C trough by 42% further NFV dose reductions are not recommended.

This study provided important information from single dose interactions in HIV-negative volunteers. [5]

Reference:

1. De Maat MMR et al. A Potential Interaction between St Johns Wort and Nevirapine. Abstract 2.8. First International Workshop on Clinical Pharmacology, 30-31 March 2000. Noordwijk, Netherlands.
2. Lamotte et al. Amprenavir Plasma Concentrations are Dramatically Increased by Association to Ritonavir in Baby Doses in HIV-infected Patients: Possible Combination with Efavirenz. Abstract 2.7. First International Workshop on Clinical Pharmacology, 30-31 March 2000. Noordwijk, Netherlands.
3. Sadler et al – Phamacokinetic Drug-Interaction between Amprenavir and Ritonavir inHIV-Seronegative Individuals. Abstract 77 – 7th Conference on Retroviruses and Opportunistic Infections, San Francisco, CA.
4. Aarnoutse et al. PK Study to Investigate the Influence of Efaviranz on a BID Regimen of Indinavir/Ritonavir (800/100mg) in Healthy Volunteers. Abstract 2.3. First International Workshop on Clinical Pharmacology, 30-31 March 2000. Noordwijk, Netherlands.
5. Hsu A et al. Interaction of ABT-378/ritonavir with Protease Inhibitors in Healthy Volunteers. Abstrat 2.4. First International Workshop on Clinical Pharmacology, 30-31 March 2000. Noordwijk, Netherlands