HTB South

Pharmacokinetics of old and new TB Drugs

Polly Clayden, HIV i-Base

Several studies at IAS 2012 showed pharmacokinetc (PK) data for older and investigational TB drugs, particularly in the context of treating HIV.

Efavirenz and rifampicin

ART and TB treatment must be given together particularly in people with advanced HIV but doing so is complicated by drug-drug interactions. Rifampicin upregulates several cytochrome P450 enzymes and has been associated with a decrease of approximately 30% trough levels of efavirenz (Cmin), when the two drugs are given together. Conversely, in African people particularly, CYP2B6 polymorphisms have been associated with paradoxical increases in efavirenz levels.

The reports of reduction in exposure led the FDA to recommend a dose increase earlier this year from 600mg to 800 mg once daily of efavirenz when co-administered with rifampicin for people weighing >50 kg. Clinical data have not shown reduced virologic suppression with 600 mg efavirenz plus rifampicin.

STRIDE (US Adult AIDS Clinical Trials Group A5221) was an international randomised trial of immediate (2 weeks after starting TB treatment) versus early (8 to 12 weeks) ART among HIV positive people with CD4 <250 cells/mm3 treated for TB. Participants were stratified to those <50 versus >50 cells/mm3 CD4. For people with <50 cells/mm3 CD4, immediate ART resulted in lower rates of AIDS and death compared to early ART but immediate ART did not result in a reduction of AIDS and death overall.

Annie Luetkemeyer from the trial group showed findings from a PK analysis of STRIDE participants receiving 600 mg efavirenz, regardless of weight, plus rifampicin-based TB treatment. [1]

In this substudy, efavirenz Cmin was determined using high performance liquid chromatography with a lower limit of detection of 0.1 mg/L. Samples were obtained 20-28 hours post-dose at weeks 4, 8, 16 and 24 on RIF, and weeks 4 and 8 off rifampicin, in participants with no missed doses for 3 days prior to sampling.

There were a total of 780 participants and 543 provided one or more efavirenz PK value. At baseline they (n=543) were a median age of 34 years, weight 52.8 kg, BMI 19.4 kg/m2 and CD4 count 64 cells/mm3. Seventy four percent were black, 20% Hispanic, 5% white and 1% Asian.

When the investigators looked at the effect of weight on efavirenz Cmin in participants on rifampicin, they found they had a median of 1.96 (IQR 1.24 to 3.79) mg/L overall. The difference in efavirenz Cmin between those weighing more or less than 50 kg was not significant. But for those weighing less than 60 kg the median efavirenz Cmin was 2.02 (IQR 1.29 to 4.09) mg/L compared to 1.68 (IQR 1.07 to 3.06) mg/L in participants above this weight, p=0.02.

There were no significant differences in efavirenz Cmin on versus off rifampicin across all weight comparisons. There was a difference however for black patients on rifampicin (n=367) who had a median efavirenz Cmin of 2.1 mg/L compared to off rifampicin (n=269) when this value was 1.8 mg/L, p=0.01. Comparisons in other ethnic subgroups were not significant but the numbers were small.

Concomitant ART and TB treatment did not effect viral load suppression <400 copies/mL. By week 48, 75.8% of participants were suppressed (n=780, but Dr Luetkemeyer remarked that this was similar in the substudy). There was no statistically significant difference in proportions of participants who were suppressed comparing those above and below 50 kg. But a significantly higher proportion of participants weighing over 60kg had a suppressed viral load compared to those weighing less, 81.9% versus 73.7%, p=0.02. Dr Luetkemeyer noted that higher weight was a marker for better health overall in the study.

When the investigators looked at efavirenz Cmin outside the therapeutic window they found subtherapeutic concentrations (<1 mg/L), were not associated with rifampicin and occurred in 27.3% versus 26.2% on and off respectively, p=0.72. Nor were they associated with weight.

Supratherapeutic efavirenz Cmin (>4 mg/L), observed in 19.6% on versus 18.8% off rifampicin, p=0.76, was not associated with rifampicin either. However, the proportion of black participants with supratherapeutic concentrations on rifampicin was significantly greater than in white participants, 22.9% versus 3.9%, p=0.02.

This finding is likely to be due to genetic differences in metabolism. Data from genetic evaluations of CYP2B6 variants were not presented.

Dr Luetkemeyer concluded that these data do not support weight based increase of efavirenz during rifampicin-based TB treatment.

Efavirenz and rifampicin in pregnancy

In the same session, Kelly Dooley from the TSHEPISO study group described the PK and pharmacodynamics (PD) of efavirenz among pregnant women. [2]

Efavirenz is being used more and more in pregnancy. In Soweto, where the TSHEPISO study is being conducted, about 1 to 2 % of HIV-positive pregnant women have active TB, yet there are few data describing the combined effect of pregnancy and rifampicin on efavirenz levels.

TSHEPISO is an ongoing prospective cohort study of HIV positive pregnant women with (n=250 cases) and without TB (n=500 controls). Women are enrolled at 13 to 34 weeks gestation. Women (n=150) with and without TB, receiving once daily efavirenz-based ART at 600 mg will enrol in an efavirenz PK/PD substudy, with their infants. Dr Dooley showed preliminary results from 76 women and 70 infants evaluated in this substudy to date.

Sampling is performed at 37 weeks gestation or at delivery and then six weeks post-partum. Efavirenz levels are also measured in cord blood at delivery and in infants at 7 days. Plasma concentrations are determined by liquid chromatography-tandem mass spectrometry Women also have CYP286 genotyping and are categorised as extensive, intermediate, slow or very slow metabolisers. Maternal viral load is measured at delivery and in infants at six weeks of age.

The case (n=33) and control (n=43) study participants were similar at enrollment with median values of approximately: 30 years of age, 30 weeks gestation and 300 cells/mm3 CD4. There were differences between the groups in the proportion with a viral load less than 20 copies/mL: 28% and 58% in the cases and controls respectively. This difference is probably explained by the delay in starting ART among those needing treatment for TB. At delivery the median time on efavirenz was 12 and 21 weeks for the cases and controls respectively, and delivery occurred at approximately 38 to 39 weeks in both groups. Distribution of CYP286 metaboliser status was also similar between the groups.

The median maternal efavirenz Cmin pre/intrapartum (n=59) was 1.4 (IQR 0.99 to 1.89) mg/L, at this time point 25.4% had an efavirenz Cmin of <1 mg/mL. At 6 weeks post partum (n=50), these values were 1.68 (IQR 1.22 to 2.7) mg/L and 20%.

Comparing on (n=30) and off (n=46) rifampicin, efavirenz Cmin were respectively 1.76 (IQR 0.89 to 3.13) and 1.52 (IQR 1.14 to 2.02) mg/L. Proportions of women with an efavirenz Cmin of <1 mg/mL were 29.1% and 17.1%.

By metaboliser status, 56.3% extensive, 5.7% intermediate, 16.7% slow and 0% very slow metabolisers had a Cmin of less than <1mg/L.

Like the study above, this analysis showed no significant differences in efavirenz Cmin on versus off rifampicin across all weight comparisons. The median Cmin of efavirenz was 1.91 in women both above and below 60kg on rifampicin, but a smaller proportion of the women who weighed <60 kg had Cmin <1mg/L, 20% versus 31.6%. Women off rifampicin weighing <60kg had a median efavirenz Cmin of 1.33 (IQR 1.12 to 1.64) mg/L compared to 1.55 (IQR 1.13 to 2.07) mg/L in those >60 kg; 11.1% and 16.7% had a Cmin < 1mg/L, respectively.

Cord blood samples were available for 45 infants and had a median efavirenz concentration of 1.15 (IQR 0.628 to 1.91) mg/L, of these 4 (8.9%) were below the limit of quantification (BLQ). At 7 days samples were available for 57 infants and the median efavirenz concentration was BLQ (IQR BLQ to 0.079) mg/L; 35/57 (61.4%) were BLQ. Quantifiable values were related to larger cord blood concentrations. Cord blood and maternal pre-partum concentrations were highly correlated (r=0.93).

At delivery 70% of cases and 83% of controls had a viral load <20 copies/mL, p=0.24. Of women receiving efavirenz for at least 12 weeks at delivery, 82% of cases and 93% of controls had viral load <20 copies/mL, p=0.26. There were no vertical transmissions among women receiving efavirenz at delivery

Raltegravir as a possible alternative to efavirenz

Raltegravir might offer an alternative to efavirenz for people needing concomitant HIV and TB treatment. This antiretroviral is not metabolised by CYP450, however rifampicin does induce the UGT 1A1 pathway and a previous study in healthy volunteers showed 61% and 40% reductions in raltegavir Cmin and AUC. This was partially compensated by a dose increase of raltegravir from 400 mg to 800 mg twice daily.

The Reflate Study (ANRS 12 180) is investigating the efficacy of these two doses of raltegravir compared to efavirenz in people also receiving rifampicin-based TB treatment in France and Brazil.

Nathalie De Castro from the study group presented 24-week data from Reflate – a multicentre, open-label, randomised, phase 2 trial. [3] Antiretroviral naïve HIV positive adults were randomised to receive raltegravir, at 400 mg or 800 mg twice daily, or efavirenz 600 mg once daily, in regimens with tenofovir and 3TC, having started TB treatment. The primary endpoint was the proportion of participants with viral load <50 copies/mL at week 24 using a modified ITT TLVOR analysis. The trial was 80% powered to show >70% success at this time point.

A total of 179 people were screened and 155 randomised – 52 to raltegravir 800 mg, 51 to raltegravir 400 mg and 52 to efavirenz 600 mg. At baseline the majority (73%) of participants were men, with a mean age of 38 years, a median viral load of approximately 5 log copies/mL and median CD4 count of 140 cells/mm3. The majority (85%) had pulmonary TB and about half were confirmed cases; participants received rifampicin-based TB treatment for a median of 6 weeks before starting ART.

At week 24 78% (95% CI 67 to 90), 76% (95% CI 65 to 88) and 63% (95% CI 49 to 76) participants had viral load <50 copies/mL in the raltegravir 800 mg, 400 mg and efavirenz arms respectively. The majority of treatment failures were virological and this occurred in 4, 12 and 15 participants, in the raltegravir 800 mg, 400 mg and EFV arms respectively. Adverse events leading to treatment discontinuation occurred in 3 participants in the raltegravir 800 mg and 2 in the efavirenz arms; there were 2 deaths in each of these respective arms (4 overall).

There was slightly more raltegravir, 3TC and tenofovir resistance in the 400 mg (4/5) than 800 mg (1/2) arm – but only tiny numbers were analysed. Resistance was present in 4/6 of the participants analysed who received efavirenz. All arms had greater than 150 cells/mm3 CD4 increase in CD4.

The investigators concluded that raltegravir seems to be a suitable alternative to efavirenz for HIV-TB co-infected patients and the optimal dose has yet to be defined based on the PK sub-study and 48 week follow-up data

Bedaquiline and rifapentine not recommended together

Dan Everitt from the TB Alliance presented data from a drug-drug interaction study of bedaquiline (TMC 207) to evaluate the effect of rifapentine on bedaquiline PK. [3]

Bedaquiline) is a diarylquinoline in development to treat drug-sensitive and drug-resistant tuberculosis. The innovator company, Janssen submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) in June 2012, seeking accelerated approval for the use of bedaquiline as an oral treatment, to be used as part of combination therapy for pulmonary, MDR-TB in adults.

It is being studied in novel combinations with the aim to minimise adverse interactions with ART. Drug-drug interaction studies have been conducted with nevirapine – which did not significantly affect bedaquiline exposure – and efavirenz – which decreased its exposure by 18% with 14 days co-administration in healthy volunteers.

A previous evaluation showed exposure of bedaquiline decreased by 52% after 7 days of rifampicin – a potent inducer of CYP3A4. And exposure of M2 decreased by 25%. In vitro and in vivo studies suggested the induction potential of CYP3A4 might be less with rifapentine.

This was a two-period, single-sequence drug interaction study in two groups of healthy subjects. The first period evaluated the PK of bedaquiline and its M2 metabolite after a single 400 mg dose. The second period evaluated the effects of repeated doses of either rifampicin or rifapentine on the PK of bedaquiline and M2. Subjects took 600 mg rifapentine (Group 1) or 600 mg rifampicin (Group 2) once daily for 22 days. A single 400 mg dose of bedaquiline was given on day 10 of the second period followed by 14 day PK sampling.

A total of 32 subjects were enrolled and 29 completed the study. Rifapentine reduced both the AUC and Cmax of bedaquiline giving 62.2% and 42.8% mean ratios respectively. The effects on M2 were similar.

Given this reduction in exposure of over 50%, the TB Alliance and Janssen will not be conducting further studies of bedaquiline with either rifampicin or rifapentine and recommend that they are not given together.

No clinically relevant interactions between delamanid and lopinavir/ritonavir or tenofovir

Delamanid (OPC-67683), a novel nitro-dihydro-imidazooxazole derivative, in phase 3 of development by Otsuka for the treatment of MDR-TB, including in people with HIV receiving ART. Delamanid is metabolised by plasma albumin and to a lesser extent CYP3A4.

Tenofovir is not metabolised by CYP enzymes and does not affect CYP3A4. Lopinavir/ritonavir is generally contraindicated with drugs metabolised by CYP3A because of potent CYP3A inhibition by ritonavir and with potent CYP3A inducers that may reduce lopinavir efficacy. Delamanid and its major metabolites neither inhibit nor induce CYP enzymes.

In a poster authored by Anne Paccaly and colleagues on behalf of the sponsor, findings were shown from a phase 1, open-label randomised, multiple dose parallel group trial investigated the drug-drug interaction potential of delamanid 100 mg twice daily and tenofovir or lopinavir/ritonavir at standard doses. In this trial, healthy volunteers aged 18 to 45 years (similar numbers of men and women) were assigned to treatment groups: delamanid (n=11), tenofovir (n=12), lopinavir/ritonavir (n=11), delaminid and tenofovir (n=13), delaminid and lopinavir/ritonavir (n=12), for 14 days to reach steady-state exposure.

Samples were taken pre-dose, days 12-13 and day 14 (full PK profile). Delamanid and metabolite plasma concentrations were determined by ultraperformance liquid chromatography-tandem mass spectrometry and ARVs by high performance liquid chromatography-tandem mass spectrometry. PK parameters and geometric mean ratios for Cmax and AUCt with 90% CI were determined.

The evaluation found that delamanid did not affect tenofovir, lopinavir or ritonavir drug exposure. Tenofovir had no effect on delamanid exposure, while a slightly higher (20%) delamanid exposure was seen with lopinavir/ritonavir, possibly related to CYP3A inhibition by RTV. Delamanid metabolites were not affected by tenofovir nor markedly affected by lopinavir/ritonavir. No changes in drug exposure occurred were considered to be clinically relevant.

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The first efavirenz presentation above ended with a welcome discussion on toxicity as Dr Luetkeymeyer was asked whether data was collected on CNS side effects as some people had “astronomically high” efavirenz levels. She explained that the investigators were looking at discontinuations, of which there were 18 in the substudy, and these were expected to be associated with CNS toxicity. Five of the participants who discontinued had efavirenz levels in the toxic range. But she noted that this represented only 5 of 92 patients with toxic levels discontinuing as a result. She explained that: “In many clinical studies, especially in resource limited settings people will do a lot to continue their ART and suffer a lot of side effects. Obviously we don’t recommend this but they often feel that it is their only chance to get these meds.” Hopefully these remarks will resonate with researchers and implementers, as so often, side effects, particularly those that depend on patient reporting, are under managed or ignored in poor (and rich) settings, despite much evidence to suggest their occurrence. The investigators are looking at patients with toxic levels who did not discontinue efavirenz.

The data on efavirenz-based ART and TB treatment in pregnancy are welcome as this is happening more and more. Women need to initiate ART early enough to have time to achieve a suppressed viral load by delivery and earlier initiation of ART is now recommended in the presence of TB treatment.

Based on the findings of these efavirenz/rifampicin interaction studies, the FDA recommendation should be revisited.

Raltegravir might well be an interesting alternative to efavirenz in the setting of treatment for HIV/TB coinfection, but for most countries with a high burden of TB its exorbitant price and limited availability might make this a merely theoretical option. Raltegravir costs over R800 per month (including VAT) in the South African private sector.

The development of bedaquiline with other TB drugs is ongoing. The NC-003 study – which will combine bedaquiline with combinations of PA-824, clofazinamine and pyrazinamide and compare them to standard of care (isoniazid, rifampacin, pyrazinamide and ethambutol), – starts in September in South Africa. The Janssen phase 3 study will permit HIV positive people on ART to enroll, including people receiving ritonavir boosted PIs and efavirenz who will be closely monitored.

It is important that sponsors developing the new TB drugs continue to look at possible drug-drug interactions with other old and new TB drugs and ART. The data from the drug-drug interaction study with delamanid and efavirenz will be presented at the upcoming ICAAC meeting.

References:

All references are from the 19th International AIDS Conference. 22-27 July 2012. Washington DC.

  1. Luetkemeyer AF et al. Relationship between weight, efavirenz (EFV) concentrations and virologic suppression in HIV+ patients on rifampin (RIF)-based TB treatment in the ACTG 5221 STRIDE study. Oral Abstract MOAB0301.
    http://pag.aids2012.org/flash.aspx?pid=1414
  2. McIlleron H et al. Efavirenz (EFV) concentrations in pregnant women taking EFV-based antiretroviral therapy (ART) with and without rifampin-containing tuberculosis (TB) treatment: the TSHEPISO Study Team. Oral Abstract MOAB0303.
    http://pag.aids2012.org/flash.aspx?pid=1284
  3. Grinsztejn B et al. A randomised multicentre open-label trial to estimate the efficacy and safety of two doses of raltegravir (RAL) to efavirenz (EFV) for the treatment of HIV-TB co-infected patients: results of the ANRS 12 180 Reflate TB trial. Oral abstract THLBB01.
    http://pag.aids2012.org/flash.aspx?pid=1079
  4. Everitt D et al. Pharmacokinetic interaction between the investigational anti-tuberculosis agent TMC207 and rifampicin or rifapentin. Oral Abstract MOAB0304.
    http://pag.aids2012.org/flash.aspx?pid=1079
  5. Paccaly A et al. Absence of clinically relevant drug interaction between delamanid, a new drug for multidrug-resistant tuberculosis (MDR-TB) and tenofovir or lopinavir/ritonavir in healthy subjects. Poster abstract WEPE043.
    http://pag.aids2012.org/abstracts.aspx?aid=19730

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