Pharmacokinetic papers from 10th CROI

Graham McKerrow and Simon Collins, HIV i-Base

The following is a summary of research into the pharmacokinetics of HIV treatment presented at the 10th Conference on Retroviruses and Opportunistic Infections (CROI) at Boston, 10-14 February 2003.

Lower dose ddI with tenofovir results in similar drug exposure to a higher ddI dose alone

Researchers at Gilead Sciences conclude from a study in 28 patients that the administration of ddI EC (didanosine, Videx) 250mg with TDF (tenofovir DF, Viread) staggered or simultaneously with or without a meal results in similar ddI exposures to a 400mg dose of ddI EC alone.

Previous studies have identified increased ddI exposure when the two drugs are co-administered. ddI dose reduction may reduce ddI-associated adverse events. The objective of the study was to evaluate ddI PK following a dose reduction when ddI is administered in the fasted state and TDF is administered with a meal per current dosage and administration instructions. The study also evaluated the PK of ddI following a simplified dosing regimen of simultaneous co-administration in both fasted and fed state.

The researchers found that when administered in a staggered fashion a 250mg dose of ddI EC plus TDF resulted in an equivalent AUC to 400mg dosed alone. ddI AUCs were slightly higher (+14%) and lower (-11%) when simultaneously co-administered with TDF in the fasted and fed states, respectively. Observed ddI Cmax values were only slightly lower following 250mg plus TDF versus a 400mg dose alone. Within the interaction with TDF, ddI exposure was minimally affected by either staggering of doses or the effect of food.

Ref: B. P. Kearney, E. Isaacson, J. Sayre, et al. Didanosine and tenofovir DF drug-drug Interaction: assessment of didanosine dose reduction. 10th Conference on Retroviruses and OIs, Boston 2003. Poster 533

Atazanavir and ritonavir plasma levels reduced by up to 25% when tenofovir is added to salvage regimen

Plasma levels of both atazanavir (ATV) and ritonavir (RTV, Norvir) seemed to be reduced in patients on salvage therapy after the introduction of tenofovir DF (TDF, Viread), according to researchers in Paris who conducted a prospective, open label, multi-centre trial of treatment-experienced patients. TDF and an RTV-enhanced ATV regimen were combined as salvage therapy; the PK part of this study is described in the poster.

The study looked at patients with HIV RNA >10,000 copies/ml after failure of regimen lines containing at least two PIs and one NNRTI. For the first two weeks patients were randomised to unchanged PI and NRTIs (group 1) or to a combination of ATV (300mg once a day), RTV (100mg once a day), and unchanged NRTIs (group 2). From weeks 2–26, all patients received ATV/RTV, TDF 300mg (once a day) and recycled NRTIs. Fifty-three patients were randomised in the study. Samples for ATV and RTV PK were drawn at week two and week six in 11 patients from group 2. Ten male patients (mean 45 years) completed the PK study.

Geometric mean at week two and six and their ratio (standard 90%CI), median and range of Tmax) are shown in Table 2 below.

The researchers conclude: “At week two, ATV PK parameters when combined with RTV are in agreement with data obtained in healthy volunteers. After TDF introduction, both ATV and RTV parameters seemed to be reduced. These preliminary findings suggest that decrease in ATV concentrations at week six could result from lowered RTV concentrations, even though the differences on most parameters did not reach statistical significance. The impact of TDF on ATV PK when given alone is unknown. Mechanism of this interaction, likely to occur at the absorption level, needs further investigation.”

Ref: A. M. Taburet, C. Piketty, L. Gérard et al. Pharmacokinetic parameters of atazanavir/ritonavir when combined to tenofovir in HIV infected patients with multiple treatment failures: a sub-study of Puzzle2-ANRS 107 Trial. 10th Conference on Retroviruses and OIs, Boston 2003. Poster 537.

Lopinavir/r and phenytoin levels both significantly reduced when coadministered

The co-administration of LPV/r (lopinavir/ritonavir, Kaletra) and the anticonvulsant phenytoin (PHT, Dilantin) used in the treatment of epilepsy, results in a two-way drug interaction whereby both LPV/r and PHT concentrations are decreased, researchers in North Carolina, Kansas and at Abbott Laboratories in Illinois conclude from their open-label, randomised, two-period crossover, steady-state PK study. Regimens may need to be adjusted as a result.

The study had two arms. Arm A (n = 12) received: Day (D) 1–10: LPV/r 400/100mg BID; D 11–22: LPV/r 400/100mg BID + PHT 300mg QD and Arm B (n = 12) received: D1–11: PHT 300mg QD; D 12–23: PHT 300mg QD + LPV/r 400/100mg BID.

Trough and AUC levels for lopinavir and phenytoin and trough levels of ritonavir all significantly decreased between day 11 and day 22 by approximately 25-50%.

The researchers conclude: “PHT appears to increase LPV clearance, which is not offset by ritonavir present in the formulation. LPV/r appears to induce metabolism of PHT. This two-way drug interaction is likely to be clinically significant, particularly for those with reduced viral susceptibility to LPV. Dosage or medication regimen adjustments may be necessary for optimal management.”

Ref: M. L. Lim, S. S. Min, J. J. Eron et al. A Two-way Drug Interaction Between Lopinavir/Ritonavir and Phenytoin. 10th Conference on Retroviruses and OIs, Boston 2003. Poster 535

Food intake essential when using NFV

An exploratory PK study of the effect of food intake on single dose NFV (nelfinavir, Viracept) concludes that: “food intake has a marked effect on nelfinavir PK with the highest levels achieved after the greatest food intake.” The need for food intake with NFV has been established, but the effect of varying food intake on optimising pharmacokinetics has not been well studied.

Researchers from Agouron Pharmaceuticals and Pfizer conducted a phase 1, randomised, open label crossover study to evaluate the impact of total kilocalories and fat content on single dose PK parameters of the NFV 250mg tablet formulation in 24 normally healthy volunteers. The four food intakes studied were: fasting; 125kcal with 20% fat; 500 kcal with 20% fat and 100kcal with 50% fat.

Nelfinavir AUC and Cmax approximately doubled with the lightest meal and increased 3-5 fold with meals containing 500-1000 kcal and 20%–50% fat.

The researchers also noted that: “M8 concentrations rose with increasing food intake, but the percentage of M8 relative to nelfinavir remained the same, approximately 15%-20%. The contribution of different quantities of fat intake on PK and the effect of food on steady state PK in HIV patients require further study.”

Ref: C. Petersen, E. Pun, R. Strada et al. Pharmacokinetics of nelfinavir (Viracept 250 mg tablet): effect of food intake on single-dose PK parameters. 10th Conference on Retroviruses and OIs, Boston 2003. Poster 544


Without detailed information on diet and food interactions it is impossible for patients to know whether they are actually being adherent, and this information should clearly be part of the initial data required for approval. When low nelfinavir plasma levels were found in the ATHENA study, the first recommendation was to confirm that dietary advice was being followed, and this alone led to achieving normal levels in about 50% of cases.

It is always essential for ‘food’ to be defined when required to obtain reliable and stable drug absorption.

Tenofovir does not influence the PK of d4T XR

TDF (tenofovir, Viread) did not influence the PK of d4T XR (stavudine, Zerit extended release) Bristol-Myers Squibb researchers conclude from a study. D4T XR does not require dose modification when co-administered with TDF, they say.

A single centre, open label study looked at the effect of the once-daily formula of d4T and TDF co-administration on the PK of d4T XR and TDF in 18 healthy subjects. On day 1: subjects received a single 100mg oral dose of d4T XR with a light meal (373 kcal). Days 2–8: subjects received once-daily 300mg oral dose of TDF with a light meal (373 kcal). Day 9: subjects received a single 100mg oral dose of d4T XR with 300mg of TDF and a light meal (373 kcal). Serial blood and urine samples were collected at selected times over a 24-hour period on days 1, 8, and 9 for PK assessments

The researchers report that plasma d4T concentration-versus time profile for the d4T XR+TDF treatment was super-imposable on the profile for the d4T XR alone treatment. The geometric mean (%CV) for Cmax and AUC, and median Tmax values were 274 (31%) ng/mL, 2,682 (29%) ng.h/mL, and 5 h, respectively, for the d4T XR alone treatment; the corresponding values for the d4T XR+TDF treatment were 275 (26%) ng/mL, 2,765 (28%), and 4 h, respectively.

Ref: S. Kaul, K. Bassi, B. Damle et al. Lack of interaction between stavudine extended-release formulation and tenofovir disoproxil fumarate. 10th Conference on Retroviruses and OIs, Boston 2003. Poster 534

Use of PIs in transplant patients increases cyclosporine AUC, requiring dose reduction

The use of protease inhibitors in HIV-positive transplant patients “markedly” increases the AUC of the immunosuppressant agent cyclosporine (CsA, Neoral; Sandimmune), and requires progressive dose reduction, conclude researchers at the University of California at San Francisco who studied CsA-ARV interactions.

The researchers also concluded: “PI values may be low at baseline, and addition of CsA post-transplant may further lower PI levels, although this effect seems to diminish over time. Little interaction between CsA and NNRTIs were observed.”

PK studies were obtained in 17 HIV-positive liver and kidney transplant subjects pretransplant, and during weeks 1–2, 4–8, 12, 28, and 52 and year 2 post-transplant. All subjects were on protease inhibitors (PIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) or both; CsA was added post-transplant.

Pretransplant PI AUCs tended to be approximately 20% below the literature mean AUC for each PI measured (indinavir, nelfinavir, saquinavir), and decreased further during the first 12 weeks post-transplantation, before returning to pretransplant values. The exception was lopinavir/ritonavir (LPV/RTV) AUCs, which were five to six times higher than the literature mean for LPV AUC, and up to three times higher than that for RTV pretransplant through week 12. NNRTI (efavirenz, nevirapine) AUCs were generally near the literature mean AUC both pre- and post-transplant. CsA AUCs were generally lower for patients on any ARV compared to CsA AUCs in HIV-negative transplant patients, especially in the first few weeks after transplantation. Over time, for patients on PIs, the CsA dose had to be decreased by more than 75% to maintain CsA AUCs within range, while CsA dose and AUCs remained essentially unchanged for patients on NNRTIs. Despite the decreasing dose of CsA for those on PIs, the amount of CsA delivered, when adjusted for dose and body weight, was at least twice that for NNRTIs, due to progressive increases in intestinal CsA bioavailability.

Ref: L.A. Frassetto, M. Baloum, M.E. Roland et al. Two-year evaluation of the interactions between antiretroviral medication and cyclosporine in HIV+ liver and kidney transplant recipients. 10th Conference on Retroviruses and OIs, Boston 2003. Poster 540

The PK of adding IDV to LPV/RTV regimens

Adding IDV (indinavir, Crixivan) 400mg BD to LPV/RTV (lopinavir/ritonavir, Kaletra) containing regimens did not significantly alter median LPV PK parameters in a British-Canadian study. However, wide inter-patient variability existed. IDV concentrations in blood plasma (BP) (Cmin), cerebro-spinal fluid (CSF), and seminal plasma (SP) were above target concentrations in 5/8, 4/4, and 3/4 samples, respectively.

Combination therapy including three protease inhibitors may be an option for drug-experienced patients. However, drug interactions can lead to toxicities or sub-therapeutic drug concentrations. Researchers at Birmingham, Liverpool and Toronto hypothesised that adding IDV 400mg BD to LPV/RTV would result in therapeutic concentrations of both drugs in the BP and therapeutic levels of IDV in CSF and semen.

Ten HIV-1-positive men on LPV/RTV (and at least one NRTI, and 3 with NVP) participated in a PK study. Sampling was performed prior to and two weeks after adding IDV to stable regimens. Blood was drawn at 0h and then 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 10, and 12 hours post-observed drug intake. CSF and semen were obtained 12 hours post-drug intake. BP, CSF, and seminal plasma (SP) drug concentrations were determined by validated HPLC-MS/MS.

No significant differences in LPV/r parameters were found when co-dosed with 400mg IDV (LPV Cmax, Cmin, AUC 0-12h increased by 9%, 46% and 20% respectively, all not statistically significant). Marked inter-patient variability was reported in LPV concentrations in plasma. All CSF samples of LPV were below the limit of detection without IDV but these rose to significant levels following IDV use.

IDV concentrations were above protein corrected minimum levels in all patients in semen and 7/8 patients in plasma. IDV levels in all CSF samples were in excess of non-protein corrected IC95 levels.

Virologically, the addition of IDV suppressed plasma viral load to <50 copies/mL in 2/8 men with detectable levels on LPV/r and 2/4 men with low level viraemia in semen became undectectable <400 copies/mL.

Ref: Isaac A, Taylor S, Rubin G et al. Lopinavir/ritonavir combined with twice-daily indinavir: pharmacokinetics in blood, CSF, and semen (The Protect Study). 10th Conference on Retroviruses and OIs, Boston 2003. Poster 531


This very interesting study suggests an intensification strategy that should involve minimal toxicity and low cost. The clinical implications of drug penetration to sanctuary sites is still poorly understood, but remains a concern for long-term treatment success and should be the focus for further study.

The study produces important information given the increased use of multiple PI therapy, especially in treatment experienced patients, but also for treatment naïve patients looking to reduce reliance on nucleosides.

NFV (nelfinavir, Viracept) decreases the bioavailability of both LPV and RTV (lopinavir, ritonavir, Kaletra), while LPV/r (Kaletra) increases dose-normalised bioavailability of NFV and M8, according to research carried out by Abbott Laboratories.

The Abbott researchers conclude that: “The dose of LPV/r may need to be increased when co-administered with nelfinavir, particularly in HIV patients with extensive protease inhibitor experience or reduced viral susceptibility to LPV. Concentrations of nelfinavir are similar when dosed at 1000mg BID with LPV/r compared to NFV 1250mg BID alone.”

Ref: C. Klein, R. Bertz, E. Ashbrenner, T. Chira et al. Assessment of the multiple-dose pharmacokinetic interaction of lopinavir/ritonavir with nelfinavir. 10th Conference on Retroviruses and OIs, Boston 2003. Poster 536

No significant interaction between enfuvirtide and saquinavir/r, ritonavir or rifampicin

Co-administration of ENF (enfuvirtide, T20) with SQV/r (ritonavir boosted saquinavir), RTV (ritonavir alone), or the anti-tuberculous agent rifampicin did not lead to clinically relevant interactions and was well tolerated, according to three international PK studies.

ENF is the most clinically advanced in a new class of drugs, the HIV-1 fusion inhibitors. It is administered subcutaneously at a dose of 90mg BID. As a synthetic peptide, it is not expected to be subject to drug-drug interactions experienced by many of the conventional antiretrovirals (ARVs). The researchers conclude: “Consistent with the expectations of a peptide drug, low potential for drug-drug interaction is confirmed for ENF by these investigations.”

Ref: M. Boyd, K. Ruxrungtham, X. Zhang et al. Enfuvirtide: investigations on the drug interaction potential in HIV-infected patients. 10th Conference on Retroviruses and OIs, Boston 2003. Poster 541

Pharmacokinetics and pharmacodynamics of low-dose mycophenolate mofetil in early stage HIV

Mycophenolate mofetil, (CellCept) the immunosuppressant used in patients receiving kidney transplants, has been proposed to increase the potency of some antiretroviral agents. An international study compared the pharmacokinetics and pharmacodynamics of two doses: 250mg BID and 500mg BID.

The researchers conclude: “Sera from the majority of patients receiving low doses of mycophenolate mofetil (250mg or 500mg BID) inhibit lymphocyte proliferation during most of the interdose intervals despite low MPA plasma levels. For some patients higher doses could be necessary, the capacity of sera to inhibit CEM proliferation can help to identify those patients. Cmax is the only parameter higher in 500mg BID vs 250mg BID, while the AUC, Cmin or inhibition of lymphocyte proliferation were similar in both groups.”

Ref: J. Martorell, M. Brunet, F. García et al. Pharmacokinetics and pharmacodynamics of low-dose mycophenolate mofetil in early stage HIV-infected patients successfully treated with HAART. 10th Conference on Retroviruses and OIs, Boston 2003. Poster 538.

Mycophenolate mofetil lowers plasma nevirapine concentrations but has no effect on intracellular triphosphate concentrations of 3TC and abacavir

Recent studies suggest a potential role for mycophenolate mofetil (MMF) in the treatment of HIV-1. MMF interferes with cellular guanosine nucleotide biosynthesis, thereby limiting lymphocyte proliferation. This might limit the availability of target cells for HIV-1 infection. In vitro MMF has a direct anti HIV-1 effect and increases the efficacy of abacavir (ABC). An international study of 14 patients looked at the effect of MMF on the pharmacokinetic parameters of a number of antiretroviral drugs, and on the intracellular deoxycytidine triphosphate (Dctp) and deoxyguanose triphosphate (Dgtp) pools and triphosphate concentrations of lamivudine (3TCTP) and ABC (CBVTP).

In this small cohort of patients, MMF reduced the plasma concentration of nevirapine but had no effect on plasma indinavir and abacavir concentrations. In contrast to the researchers’ hypothesis, there was no consistent effect of MMF on the intracellular concentrations of dCTP, dGTP, or 3TCTP. They conclude that additional PK and efficacy data are required to determine the impact of MMF when added to existing antiretroviral therapy.

Ref: S. Sankatsing, P. Hoggard, D. Back et al. Mycophenolate mofetil lowers plasma nevirapine concentrations but has no effect on intracellular triphosphate concentrations. 10th Conference on Retroviruses and OIs, Boston 2003. Poster 539

Co-administration of atazanavir and efavirenz; and the effects of atazanavir on oral contraceptives

Atazanavir (ATV) is a potent, safe, and effective once-daily azapeptide protease inhibitor currently in Phase III development. Two individual pharmacokinetic (PK) drug interaction studies were reported. The first study was conducted to assess whether efavirenz (EFV), a metabolic enzyme inducer, had an effect on ATV exposure. The second study was conducted to assess whether ATV had an effect on either ethinyl estradiol (EE) (a substrate of UDP-glucuronosyl transferase 1A1) or norethindrone (NE), a combination oral contraceptive (OC).

They also conclude: “Co-administration of OC and 400 mg ATV will not impact OC effectiveness. No dose adjustment of OC is recommended. In both studies, no serious laboratory or clinical adverse events were observed.”

Ref: D. Tackett, M. Child, S. Agarwala et al. Atazanavir: A summary of two pharmacokinetic drug interaction studies in healthy subjects. 10th Conference on Retroviruses and OIs, Boston 2003. Poster 543.

The effect of alcohol on protease inhibitor exposure in chronic heavy drinkers

The effect of ethanol (alcohol) on the PK of drugs has not been fully investigated. Twenty-five per cent of HIV-infected subjects are heavy drinkers and susceptible to drug-drug interactions between ethanol and antiretroviral therapy. Ethanol may induce cytochrome p450 (CYP) metabolism when used chronically. However, when taken acutely, ethanol will inhibit drug metabolism due to competition with CYP isozymes. It has been hypothesised that chronic ethanol use will result in diminished HIV protease inhibitor (PI) exposure while acute ethanol use will result in increased PI exposure.

Researchers in San Francisco and Seattle prospectively enrolled HIV-infected subjects managed with nelfinavir (NFV) (n = 27) or indinavir (IDV) (n = 8), to evaluate the acute and chronic effects of ethanol on protease inhibitor pharmacokinetics.

The researchers conclude that results to date suggest minimal effect of ethanol on PI exposure. The slight increase in NFV AUC with ethanol use implies ethanol co-administration can occur without risk of suboptimum PI exposure. Furthermore, there appears to be no difference in the effect of ethanol on PI PK when used chronically versus acutely.

Ref: F. Aweeka, P. Lizak, L. Karan et al. The effect of ethanol on protease inhibitor exposure in chronic heavy ethanol users. 10th Conference on Retroviruses and OIs, Boston 2003. Poster 545

Administering rifampin with IDV/RTV 800/100mg risks subtherapeutic concentrations of IDV

There is clinically significant interaction between IDV (indinavir, Crixivan) and rifampin, used in the treatment of MAC and TB infections, report Danish researchers. In their study of the pharmacokinetic interaction between rifampin and the twice-daily combination of indinavir and low-dose ritonavir in HIV-infected patients, they saw a dramatic decrease in IDV C12h. They conclude that it is not possible to administer rifampin together with the IDV/RTV 800/100mg regimen without risking subtherapeutic concentrations of IDV.

Ref: U. Justesen, A. Andersen, N. Klitgaard et al. Pharmacokinetic interaction between rifampin and the twice-daily combination of indinavir and low-dose ritonavir in HIV-infected patients. 10th Conference on Retroviruses and OIs, Boston 2003. Poster 542.

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