Pharmacology of second-line antituberculosis drugs and potential for interactions with antiretroviral agents

Introduction An estimated 33.2 million people were living with HIV worldwide in 2007 [1]. In 2006 there were an estimated 700 000 cases of tuberculosis (TB) among HIV-positive people, and 200 000 deaths [2]. HIV increases the risk of active TB and the mortality rate. When HIV-positive individuals are diagnosed with TB they usually have significant immunosuppression and require HIV therapy as well as TB treatment. First-line TB drugs are isoniazid, rifampicin, pyrazinamide and ethambutol. Co-administration with antiretrovirals often results in drug–drug interactions which may compromise efficacy or result in toxicity. Adverse effects are very common and include gastrointestinal intolerance, rashes and hepatotoxicity, which may necessitate stopping drugs and reintroducing them gradually. There are overlapping toxicity profiles such as peripheral neuropathy with isoniazid and didanosine, and anaemia with isoniazid, rifampicin, pyrazinamide and zidovudine. Whenever possible the most efficacious TB regimen should be continued, with adjustment to the antiretroviral drugs if necessary. However, sometimes it is unsafe to continue the first-line TB drugs and alternatives need to be found. Second-line TB drugs also need to be employed when Mycobacterium tuberculosis is resistant to first-line drugs. Multidrug-resistant TB (MDR-TB) is defined as a TB which is resistant to both rifampicin and isoniazid and is an emerging epidemic, with 489 000 cases annually, representing nearly 5% of the global TB burden [2]. Treatment of MDR-TB is usually continued for 24 months rather than 6–12 months for drug-sensitive TB, and second-line agents are usually much more expensive. This adds up to the cost of drugs for MDR-TB exceeding drug costs for sensitive TB by 100-fold to 300-fold [3,4]. The management of MDR-TB is especially challenging in resource-poor settings in which there is limited availability of resistance testing, expertise in complex treatment decisions, second-line agents and facilities for monitoring safety, efficacy and plasma concentrations of drugs. Adequate management of MDR-TB is crucial not only for recovery of the individual but also to prevent the acquisition of more resistance mutations, and the spread of drug-resistant strains between individuals. Extensively drug-resistant TB (XDR-TB) is defined as MDR-TB also resistant to a fluoroquinolone and at least one second-line injectable agent (amikacin, kanamycin and/or capreomycin), and is a small but growing problem. XDR-TB has a high mortality rate, especially among those infected with HIV [5]. Second-line TB drugs include some of the oldest antimicrobial agents developed, such as para-aminosalicylic acid (PAS), ethionamide and thiacetazone. When older drugs were developed, current knowledge of metabolic pathways and modern methods for screening for interactions were not available. Other classes of drugs were derived from antimicrobials produced by certain strains of actinomycetes, and include the aminoglycosides (amikacin and kanamycin), polypeptides (capreomycin, viomycin, enviomycin) and cycloserine. Some broad-spectrum antibiotics have activity against M. tuberculosis, including fluoroquinolones. There is less evidence for macrolides, amoxicillin with clavulanic acid and the newer synthetic antibacterial linezolid. The use of many of these agents has been limited by intolerability, toxicity and uncertain efficacy (see Table 1). On the positive side, this means that resistance to these drugs is uncommon.Table 1: Antituberculosis drugs grouped by World Health Organisation classification: role in treatment and adverse effects.The review will summarize the limited knowledge about pharmacology of second-line anti-TB agents, the small number of drug interactions studies which have been performed and the difficulty in predicting drug interactions. Implications for clinical practice will be discussed (see Table 2).Table 2: Second-line antituberculosis agents and antiretrovirals: a summary of the evidence for drug interactions and recommendations for use.Table 2: (continued)Interaction potential of antiretroviral drugs There are five classes of drugs currently licensed for the treatment of HIV. These are: Nucleoside reverse transcriptase inhibitors (NRTIs; abacavir, didanosine, emtricitabine, lamivudine, zidovudine) and a nucleotide reverse transcriptase inhibitor (tenofovir) Nonnucleoside reverse transcriptase inhibitors (NNRTIs; efavirenz, etravirine, nevirapine) Protease inhibitors (PIs; atazanavir, darunavir, fosamprenavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir) Entry inhibitors (the fusion inhibitor enfurvirtide, and the CCR5 antagonist maraviroc) Integrase inhibitors (raltegravir) In clinical practice, three or more drugs from at least two classes are usually employed concurrently to suppress viral replication. Pharmacokinetic interactions with antiretroviral drugs may occur during absorption, distribution, metabolism and elimination. Gastric pH, activity of transmembrane transporters such as enterocyte P-glycoprotein (P-gp) and drug metabolism by enterocyte cytochrome P450 (CYP450) enzymes may all influence the bioavailability of antiretroviral drugs. Once absorbed, antiretroviral drugs bind variably to plasma proteins (principally albumin and alpha-1 acid glycoprotein) and the extent of binding may be altered by co-administered drugs. Hepatic CYP450 enzymes are responsible for the metabolism of a wide variety of drugs. NNRTIs and PIs are extensively metabolized by CYP450 and clinically significant drug interactions with these drugs are common [6]. As well as being substrates for CYP450, efavirenz and nevirapine induce these enzymes (i.e. CYP2B6 and 3A4) and may increase clearance of other drugs. Ritonavir is a potent inhibitor of CYP3A4 used routinely to increase plasma concentrations of other PIs. Ritonavir-boosted PIs may therefore lead to higher concentrations of other drugs metabolized by CYP3A4 or other isoforms inhibited by ritonavir (i.e. CYP2D6). In contrast, NRTIs are not metabolized by CYP450. They undergo intracellular phosphorylation to the active drug and have a low potential for significant drug–drug interactions [7]. Evidence is emerging of the importance of phase II reactions in drug interactions involving antiretrovirals. Ritonavir, for example, is an inducer of glucuronidation and has been clearly shown to be responsible for significant decreases in concentrations of drugs that are eliminated via this reaction, including etravirine [8] and lamotrigine [9]. Furthermore, the effect of ritonavir on glucuronidation is dose-dependent. Distribution of drugs is also mediated by plasma membrane influx and efflux transporters including P-gp, multidrug resistance protein (MRP), organic anion transport protein (OATP1 and OATP2). These transporters are present on many cell types including intestinal epithelium, hepatocytes and kidney. They control absorption, intracellular distribution, metabolism and elimination of drug through biliary canals and active tubular secretion. Aminoglycosides Aminoglycosides including streptomycin, kanamycin and amikacin are bacteriocidal, show considerable in-vitro activity against M. tuberculosis[10] and are clinically efficacious. The potential for pharmacokinetic drug interactions is low, although additive toxicities may occur. Aminoglycosides achieve high concentrations in bone, pleural, ascetic, synovial and peritoneal fluid and show poor cerebrospinal fluid (CSF) penetration (except amikacin in children with meningitis [11]). They are excreted unchanged in urine by glomerular filtration. All cause renal dysfunction, although streptomycin has been reported to be less nephrotoxic than other aminoglycosides [12]. Whenever possible co-administration with other drugs associated with renal dysfunction should be avoided, including the NRTI, tenofovir. Aminoglycosides are ototoxic [13] and eighth cranial nerve function should be tested at baseline and during treatment. Streptomycin Streptomycin was the first effective anti-TB agent. It is given intramuscularly at a usual dose of 1–2 g daily. Therapeutic drug monitoring should be employed to maintain Cmax of 15–40 μg/ml and Ctrough of less than 5 μg/ml (Ctrough lower than 1 μg/ml in adults over 50 years old or with renal impairment). The half-life of streptomycin is 2–3 h and it is 30% protein bound. Kanamycin Kanamycin is given intravenously or intramuscularly at a dose of 15 mg/kg per min in two or three divided doses, with a dose reduction in renal impairment. It is also excreted rapidly by glomerular filtration with a serum half-life of about 4 h. Therapeutic drug monitoring may be useful, aiming for Cmax of 15–30 μg/ml and Ctrough of less than 10 μg/ml. Amikacin Amikacin is a semi-synthetic aminoglycoside derived from kanamycin and administered parenterally at a dose of 15 mg/kg per day in two or three divided doses, reduced in renal impairment. Therapeutic drug monitoring of both Cmax and Ctrough is recommended. Amikacin is excreted unchanged in urine with plasma half-life of about 2 h. Plasma protein binding is estimated at 0–11%. Polypeptides Capreomycin, viomycin and enviomycin Capreomycin, viomycin and enviomycin are not absorbed from the gastrointestinal tract and are given intramuscularly. CSF penetration is poor. They are mostly excreted unchanged by the kidney. About 50% of a dose of capreomycin is excreted by glomerular filtration within 12 h. Like aminoglycosides, the major problems are ototoxicity and nephrotoxicity. Renal function should be closely monitored, especially when co-administered with tenofovir. Fluoroquinolones Fluoroquinolones are broad-spectrum antibiotics and are tuberculocidal. Their use in TB treatment has been the subject of a recent Cochrane review [14]. Their mechanism of action is inhibition of bacterial topoisomerase IV and DNA gyrase enzymes required for bacterial DNA replication, transcription, repair and recombination. Oral bioavailability is high: ciprofloxacin 70% [15], ofloxacin 98% [16], levofloxacin 99% [17], gatifloxacin 96%, sparfloxacin 90% and moxifloxacin 90%. There is no substantial loss from first-pass metabolism. The absorption of all fluoroquinolones is reduced by buffered drugs including older formulations of didanosine, and they should be taken 2 h before or 6 h after any buffered drugs. They can also be administered intravenously. Binding to plasma proteins is moderate 20–50% [17,18], and not high enough to expect significant interactions with protein binding of other drugs. Levofloxacin, gatifloxacin and moxifloxacin may cause prolongation of the QT interval and should be used with caution with other agents that do the same, including PIs [19], efavirenz [20], clarithromycin, erythromycin and some antidepressants. If these drugs are used together electrocardiographic monitoring is strongly recommended. Ciprofloxacin Ciprofloxacin has very little anti-TB activity and a more active fluoroquinolone should be used if available. Ofloxacin, levofloxacin and gatifloxcin Levofloxacin is the optical S-(−) isomer of ofloxacin and is twice as potent in vitro[21]. Ofloxacin is widely distributed in body fluids, and penetrates CSF better than levofloxacin. Ofloxacin, levofloxacin and gatifloxacin are primarily excreted unchanged in urine [17] by active tubular secretion. Dose reduction is required in renal failure and caution should be exercised when co-prescribing drugs associated with renal dysfunction including tenofovir. Only 4–8% of the dose is recovered from the faeces. Unlike ciprofloxacin, they do not seem to have any significant effect on CYP450 activity or phase II reactions [16,22]. Sparfloxacin Sparfloxacin exhibits excellent tissue penetration with concentrations in most extracellular fluids at least as high as in plasma, although lower in CSF [18]. Sparfloxacin does not appear to interact with theophylline, caffeine, warfarin or cimetidine [18], suggesting that its metabolism does not involve CYP2E1, 1A2, 2C19 or 3A4. It is metabolized in the liver by glucuronidation with an elimination half-life of about 20 h [18]. Ritonavir induces glucuronidation and reduces the concentration of drugs metabolized by glucuronidation [9]. It would therefore be expected that ritonavir reduces concentrations of sparfloxacin. Atazanavir inhibits glucuronidation and hypothetically causes increased sparfloxacin concentrations, but this effect may be counteracted by the common co-administration of ritonavir with atazanavir. Sparfloxacin is excreted in equal amounts in faeces and urine as unchanged drug and as the glucuronide metabolite. Moxifloxacin Unlike other fluoroquinolones, 52% of an oral or intravenous dose of moxifloxacin is metabolized via sulphate conjugation and glucuronidation. The sulphate conjugate accounts for 38% of the dose, and is primarily excreted in faeces, whereas 14% is converted to a glucuronide conjugate which appears in urine [23]. The remaining drug is excreted unchanged in urine (20%) and faeces (25%). Doses do not need to be modified in renal failure. Moxifloxacin does not alter CYP3A4, 2D6, 2C9, 2C19 and 1A2 activity and should not alter antiretroviral concentrations. Concomitant administration of rifampicin caused a 27% decrease in moxifloxacin area under the curve (AUC) and a marked increase in the concentration of the inactive sulphate metabolite, probably by the induction of sulphate conjugation [24]. The clinical significance of this is unclear and antiretrovirals are unlikely to alter sulphate conjugation. Polymorphisms of the MDR1 gene, which encodes P-gp, are associated with delayed absorption of moxifloxacin, although total moxifloxacin drug exposure was unchanged [24]. This effect may also occur with ritonavir, which is an inhibitor of P-gp expression [25]. Neither the magnitude nor the clinical importance of this interaction has been investigated, and further pharmacodynamic studies are warranted. Thioamides Ethionamide and protionamide Ethionamide is administered orally with a bioavailability of over 90% [26,27]. It is started at 250 mg daily. The dose is titrated up to 15–20 mg/kg per day (maximum 1 g daily) if gastric irritation permits. It is usually given once daily but divided doses can lessen gastrointestinal symptoms. It reaches high concentrations throughout the body including in CSF, and 10–30% is protein bound [28]. Ethionamide is metabolized in the liver to seven metabolites, some of which are biologically active. Metabolism occurs by sulphoxidation, desulphuration and deamination, followed by methylation [26,27]. The involvement of CYP450 enzymes means that drug interactions are likely. Less than 1% is excreted unchanged by the kidneys. Therapeutic drug monitoring is recommended in hepatic impairment. A high incidence of hepatotoxicity has been reported when ethionamide has been used with other hepatotoxic drugs such as rifampicin [29,30]. Caution should therefore be exercised if co-prescribing antiretrovirals which have been strongly associated with abnormal liver function, including the NNRTIs efavirenz and nevirapine [31] and the PIs darunavir [32] and tipranavir [33]. Ethionamide can cause depression, anxiety and psychosis. It may therefore not be advisable to start efavirenz at the same time, since these side effects are commonly experienced in the first few weeks of efavirenz therapy [34]. A psychotic reaction has been reported with the combination of ethionamide and excess alcohol [35]. Patients should therefore be counselled to avoid excess is closely to ethionamide with mechanism of action and has a and its use is limited by side Plasma concentrations should be in those more than mg those with renal dysfunction and if toxicity should be μg/ml. increases the risk of caution should be exercised with or is and absorbed from the gastrointestinal Plasma protein binding is less than It is widely distributed throughout body fluids including CSF It is excreted unchanged by glomerular filtration with a plasma half-life of about 10 h of a dose appears in urine within 12 h and 70% by h. The is to be metabolized but the pathways are side effects include depression, and It is probably advisable not to start efavirenz acid acid was clinical use in and was the to be effective against tuberculosis, after It is use has been limited most TB does not CSF the are in which CSF concentrations of plasma concentrations It absorption of and can induce a acid is rapidly in the liver and excreted by glomerular filtration It is excreted with 50% excreted in the inactive of is protein bound and the plasma half-life is min interactions with antiretroviral agents have been is to It was shown to be against M. tuberculosis in It is well absorbed orally and protein bound. plasma half-life is h but its metabolism is not is excreted unchanged in has been widely used in resource-poor in a combination with However, about low and toxicity have limited its There have been of increased of reactions including in HIV-positive some its administration in HIV is not recommended is a as an anti-TB but primarily used as an of action are but it to DNA and inhibits It also has oral it has a very half-life of up to It is and to be in tissue and of the It does not CSF well It is eliminated unchanged in faeces, both as drug and via biliary A small is excreted in urine as unchanged drug and is a inhibitor of may absorption of rifampicin and the to with and A have also been reported with antiretrovirals are to but the potential for to increase plasma concentrations of drugs metabolized by CYP3A4 including inhibitors and with clavulanic acid antibiotics have a very limited role in the treatment of TB with clavulanic acid has been used at high doses in multidrug against TB with some is commonly used in individuals with HIV and interactions with antiretrovirals are is a semi-synthetic used to M. as well as second-line against M. When administered orally it first-pass metabolism that the bioavailability is It can also be given intravenously. is metabolized to the active and both high concentrations in in of intracellular Plasma protein binding is is extensively metabolized in the when it is both a for and an inhibitor of are mostly excreted in urine with a in faeces via between and antiretrovirals have been co-administration of reduces concentrations, but no reduction is if and are given at least 2 h should be exercised if there are other concentrations such as or interactions with other drugs. and ritonavir are both inhibitors of little on plasma concentrations of However, co-administration of ritonavir with in inhibition of the of the of and an increase in of This is unlikely to be clinically significant in with renal function, but in those with renal ritonavir, the dose of should be reduced by 50% with clearance and by with clearance less than and the daily dose should not 1 administration of and in no significant in induces CYP3A4, reduces concentrations and increases the concentration of the metabolite, associated with an increased of also reduces concentrations should therefore be of in efavirenz or is derived from It is given orally with absorption and bioavailability or intravenously. It is widely distributed in which concentrations up to 100-fold higher than plasma concentrations, and more elimination half-life of h once or once It penetrates CSF when are The metabolism of is not but is via hepatic pathways other than CYP450 enzymes It is excreted as unchanged drug in It is a less potent inhibitor of than and interactions are less likely. Co-administration of and efavirenz does not the concentration of drug increased the Cmax and of by over via inhibition of P-gp the combination was caution should be exercised when these drugs In this caused a small decrease in concentrations, which is unlikely to be clinically Ritonavir is a potent inhibitor of P-gp and may also increase although this drug combination has not been no significant on the Cmax and of although it increased the intracellular exposure to by The same that no significant effect on whereas concentrations were not may therefore be co-administered with both and is a synthetic antibacterial agent of the which has been used in against MDR-TB However, toxicities are can cause and should be used in with including those with anaemia on zidovudine. of have been associated with and or peripheral neuropathy and appear to protein It would therefore be advisable not to other which suppress activity such as didanosine, and to a extent zidovudine. is given orally with bioavailability or intravenously. binding is and there is penetration including CSF It is primarily metabolized by to two inactive of administered drug is excreted in urine as metabolites, and appears in urine as unchanged drug is not an inducer of CYP450 in and in-vitro studies have shown that is not metabolized by CYP450 and it does not the of clinically significant isoforms 2C9, 2D6, is a inhibitor of A and and should not be co-administered with inhibitors or antidepressants. Pharmacokinetic drug–drug interactions with antiretrovirals are not in agents are being with of which are active against drug-resistant They may the of and should be given to interactions with antiretrovirals in to is a which It has shown activity in clinical It is metabolized by CYP3A4 to an active metabolite. Pharmacokinetic studies of and inhibitor of an increase in of It would therefore be that concentrations increase with the inhibition of CYP3A4 by ritonavir and decrease with induction by efavirenz or include and have in-vitro activity against drug-resistant TB, no CYP450 interactions have been and results of phase II are is a drug currently in phase clinical It is metabolized by and interactions with ritonavir are likely. are a of drugs with in-vitro activity against and drug-resistant strains of M. Second-line TB drugs include agents by metabolic Some of these are among the oldest antimicrobials clinical practice, have been may interact with one or more antiretroviral Pharmacokinetic or pharmacodynamic interactions may cause toxicity and alter of the pharmacology of second-line TB drugs is to are of first-line TB drugs or are infected by MDR-TB or MDR-TB and XDR-TB are emerging and management is to be in resource-poor in which the burden of is The burden of MDR-TB and XDR-TB can be reduced by better of to rapidly and treatment in first-line TB drugs. The World Health to TB and to second-line TB treatment in is need to be to drug-resistant resistance and for second-line treatment on the of which are to These second-line should be to antiretroviral which are and have interactions. The was and by all and the and the of the and the and the management of and use of second-line anti-TB drugs. the and the on of the on of in pharmacology and the