HTB

Drug-drug interactions

1 September 2001. Related: Conference reports, PK and drug interactions, .

Polly Clayden, HIV i-Base

Several PK posters looked at antiretroviral drug-drug interactions particularly within the context of more complex therapies.

Lopinavir/ritonavir dramatically decreases amprenavir levels

In order to evaluate the reciprocal interactions, in a retrospective study, Lamotte and colleagues determined Cmin in patients receiving lopinavir (LPV) and amprenavir (APV) in the presence of ritonavir (RTV) [1]. Cmin were measured in patients using lopinavir (LPV)/RTV (400/100mg BID) plus APV (450-750mg BID) plus or minus RTV (100mg BID) plus or minus efavirenz (EFV) (600 mg QD). The resulting APV Cmin were then compared to a reference group using APV (450 or 600 mg BID) plus RTV (100-200mg BID) plus or minus EFV (600mg QD) and lopinavir C-min to those in patients receiving LPV as the sole protease inhibitor. The investigators found that compared to the referent, APV Cmin were 49-83% lower when used in combination with LPV/RTV and they concluded that the ‘LPV/RTV and APV combination did not seem to reach the expected APV Cmin for optimal antiviral efficacy on resistant strains and may compromise therapeutic response in salvage therapy’.

And negative drug-drug reaction between amprenavir and ritonavir…

It is well known that drug exposure of indinavir (IDV); saquinavir (SQV) and APV are increased by the co-administration of RTV. In a retrospective study from Guiard-Schmid and colleagues the influence of these three protease inhibitors on plasma levels of RTV were evaluated in patients using dual PI therapy [2]. RTV plasma levels were compared at Cmin and Cmax (2-4 hours post dose). All patients received 100mg RTV in combinations with either APV (600mg BID), IDV (200-800mg BID) or SQV (600-1000mg BID).

They found that in the APV group, Cmin and Cmax showed a lower inter-patient variability than in the other two groups. APV Cmin values were found to be statistically independent of RTV plasma levels. In the IDV and SQV groups however, Cmin were positively correlated (p<01.01 and p<0.05 respectively) with RTV concentrations. As compared to the IDV and SQV groups, RTV plasma concentrations were found to be statistically lower in the APV group. In addition patients also using the NNRTI efavirenz (EFV) in the APV group did not experience any RTV concentration change as compared to those in the group not treated simultaneously with this drug (p=0.5). The PK profile of APV in the presence of RTV was unaffected by the administration of EFV.

These findings suggest a negative drug-drug interaction between APV and RTV. The investigators recommend that in a situation where a third PI is administered with an APV/RTV containing combination, TDM should guide dose adjustment to avoid treatment failure. They also recommend that if APV Cmin and Cmax are low, increasing the APV dose is preferable to modifying the RTV dose.

High inter-patient variability with lopinavir and ritonavir

Another retrospective study of experienced patients, from Meynard and colleagues, evaluated the Cmin of LPV and RTV in patients receiving this boosted PI (LPV/r) at a dose of 400/100mg BID without EFV or nevirapine (NVP) [3]. The RTV Cmin were then compared to a reference group receiving RTV (100mg BID) in combination with either APV (600mg BID), IDV (200-800mg BID or SQV (600-1000mg BID).

They found a 11-fold variability of LPV Cmin between people in the study group (median = 3172ng/ml, range 849 to 9298ng/ml). A positive correlation was found between LPV Cmin and RTV Cmin (p<0.0001), similar to that in IDV and SQV groups (p<0,01 and p<0.05 respectively). However in the LPV group the RTV median Cmin was significantly lower (134ng/ml, p<0.01) than in patients using either IDV or SQV (394ng/mg and 370ng/mg respectively) and APV caused a similar significant decrease in the RTV Cmin. In addition to the inter-patient variability of LPV Cmin, these data suggest a negative drug-drug interaction between LPV and RTV as reported between APV and RTV. The investigators also recommend the use of TDM to guide dose adjustment in patients receiving dual PI therapy (with or without other PIs) to prevent treatment failure.

Drug-drug interactions with tenofovir

Flaherty and colleagues from Gilead Sciences evaluated the PK parameters of tenofovir DF (TDF), IDV, LPV/r and EFV in a steady state study in a group of healthy volunteers receiving the agents alone or in tenofovir containing pairs [4].

The study was a three way crossover design – within each of three cohorts each subject received all of the following treatments – Treatment A: TDF (300mg QD) alone; Treatment B: TDF and IDV (800mg every eight hours), LPV/r (400mg/100mg BID) or EFV (600mg QD); Treatment C: IDV, LPV/r or EFV alone. All doses were given in the fasted state except for the LPV/r cohort where all drugs were administered with food. Multiple blood samples were taken over 24 hours following the last (morning) dose of study medication in each period and PK parameters including AUCs and Cmax were calculated.

Tenofovir PK were unaffected by co administration of EFV or IDV. AUCs and Cmax ratios (90%CI) [0.96 (0.85,1.08) and 1.07 (0.94,1.22)] for EFV and (90%CI) [1.07(0.95,1.19) and 1.14 (0.97, 1.33)] for IDV. Coadministration with TDF had no effect on the AUCs and Cmax of EFV [0.96 (0.93,1.0) and 0.96 (0.91, 1.02)] or IDV [0.95 (0.82, 1.82, 1.10) and 0.89 (0.70, 1.12)]. Tenofovir AUCs and Cmax were approximately 30% higher during administration with LPV/r [1.34 (1.25, 1.44) and 1.31 (1.12 and 1.53)]. Coadministration with TDF resulted in 155 lower LPV AUCs [0.85 (0.78, 0.93)] and Cmax [0.85 (0.77,0.94)] and 11% lower Cmin [0.89 (0.78, 1.01)] – this change in the Cmin is not considered to be statistically significant.

The authors concluded that coadministration of tenofovir DF with IDV or with EFV does not result in clinically relevant drug-drug interactions and that the small changes observed in LPV PK parameters when administered with tenofovir DF are not expected to have clinical relevance.

A second Gilead study from Kearney and colleagues with the same crossover trial design investigated the PK parameters of TDF, lamivudine (3TC) and didanosine (ddI) when administered to healthy volunteers alone or in TDF-containing pairs [5].

In this study, Treatment A: TDF (300mg QD) alone; Treatment B: TDF and 3TC(150mg BID) or ddI (400mg or 250mg<60kg QD); Treatment C: 3TC or ddI alone. All doses were administered in the fasted state over seven days to achieve steady state with a seven-day washout period between treatments. ddI was taken one hour prior to TDF during the period of coadministration. Multiple blood samples were obtained and PK parameters were assessed as in the previous study.

The investigators found that coadministration with 3TC did not affect the PK of tenofovir [mean ratios (90% CI) for AUCs 0.96 (0.85. 1.08) and Cmax 1.02 (0.96. 1.09)]. Similarly there were no significant alterations in tenofovir PK when taken with ddI [AUCs 0.94 (0.86, 1.02) and Cmax 0.98 (0.82, 1.12)]. Coadministration of TDF with 3TC produced a 0.9 hour delay in Tmax of 3TC and a corresponding 24% decrease in Cmax [0.76 (0.66, 0.88)], but no difference was reported in overall drug exposure [AUCs 0.97(0.82, 1.15)]. However ddI Cmax was increased by 28% [1.28 (1.11, 1.48)] when taken with TDF and overall exposure increased by about 40% [AUCs 1.44 (1.31, 1.59)].

They concluded that coadministration of TDF with 3TC does not result in clinically relevant drug-drug interactions. Coadministration of ddI with TDF did not affect the PK of TDF but increased ddI exposure by 40%. However their assessment of available data did not suggest an increased risk of ddI adverse events when ddI is administered with TDF.

Drug-drug interactions with PIs and NNRTIs

A study from Caldwell and colleagues showed data that evaluated the prevalence of confirmed and potential drug interactions within a group of 229 patients. In addition the outcomes of the confirmed interactions were determined [6].

This group of patients who were receiving either a NNRTI and/or PI (or had done so previously) were evaluated for confirmed and potential drug-drug interactions. They described ‘confirmed drug interactions’ as drug interactions either identified in the manufacturer’s prescribing information or within existing data, and ‘potential drug interactions’ were those identified in the manufacturer’s prescribing information as warnings or cautions without specific recommendations.

A total of 411 NNRTI and/or PI containing regimens were identified within this cohort. 449 confirmed and potential interactions were identified, of which 160 could be classified as confirmed drug-drug interactions. Out of these 160 confirmed drug interactions identified, 100 were identified as synergistic interactions, ie pharmacokinetically ‘boosted’ PIs. In addition six different non-antiretroviral drug-drug interactions (n=41) were also identified with no negative outcomes.

Three patients receiving saquinavir and efavirenz within their regimens did not achieve virologic success, which could have been attributed to the drug-drug interaction.

The investigators concluded that ‘With pharmacist involvement, only 1.9% of the confirmed interactions were potentially associated with negative outcomes despite a 14.6% prevalence rate of confirmed drug-drug interactions (excluding synergistic reactions) in patients receiving PIs and NNRTIs’.

References:

  1. Lamotte, C; Peytavin, G; Duval, X. Amprenavir (APV) Plasma Concentrations are Dramatically Decreased by the Association with ABT378/r in HIV-infected patients (Pts). Abstract 334
  2. Guiard-Schmid, J; Meynard, J; Poirier, J. Drug-drug interaction specificity of amprenavir/ritonavir in dual protease inhibitor (PI) combinations. Abstract 335
  3. Meynard, J; Guiard-Schmid, J; Poirer, J. Lopinavir and ritonavir trough plasma concentrations in HIV-experienced patients treated with Kaletra. Abstract 341.
  4. Flaherty, J; Kearney, B; Wolf. A Multiple-Dose, Randomised, Crossover Drug Interaction Study between Tenofovir DF and Efavirenz, Indinavir, or Lopinavir/Ritonavir. Abstract 336.
  5. Kearney, B; Flaherty, J; Sayre. A Multiple-Dose, Randomised, Crossover Drug Interaction Study between Tenofovir DF and Lamivudine or Didanosine. Abstract 337.
  6. Caldwell, R; Delacruz, L; Montoya, J. Confirmed and Potential Drug Interactions in Patients Receiving NNRTIs and PI’s in a University-Based HIV Clinic. Abstract 338.

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