Low Potential For Drug Interactions Research Articles

Absence of Clinically Meaningful Drug-Drug Interactions with Rezafungin: Outcome of Investigations.

Rezafungin is a novel once-weekly echinocandin for intravenous injection currently in development for the treatment of Candida infections and the prevention of Candida, Aspergillus, and Pneumocystis infections in allogeneic blood and marrow transplant recipients. While in vitro data indicated that rezafungin exposure was unlikely to be affected by commonly prescribed medicines, interactions resulting in the altered systemic exposure of some drugs coadministered with rezafungin could not be excluded. Two phase 1 open label crossover studies, conducted in healthy subjects, examined drug interactions between rezafungin and multiple drug probe cytochrome P450 (CYP) substrates and/or transporter proteins, immunosuppressants, and cancer therapies. Statistical analysis compared the outcomes for drugs coadministered with rezafungin to those for the drugs administered alone. The geometric mean ratio was reported, and a default 90% confidence interval (CI) no-effect equivalence range of 80 to 125% was used for the maximal plasma concentration (Cmax), the area under the curve from time zero to the final sampling time point (AUC0-t), and the AUC from time zero to infinity (AUC0-∞). Most probes and concomitant drugs were within the equivalence range. For tacrolimus, ibrutinib, mycophenolic acid, and venetoclax, the AUC or Cmax was reduced (10 to 19%), with lower bounds of the 90% CI values falling outside the no-effect range. The rosuvastatin AUC and Cmax and the repaglinide AUC0-∞ were increased (12 to 16%), with the 90% CI being marginally above the upper bound. Overall, the in vitro and in vivo data demonstrated a low drug interaction potential with rezafungin via CYP substrate/transporter pathways and commonly prescribed comedications, suggesting that coadministration was unlikely to result in clinically significant effects. Treatment-emergent adverse events were typically mild, and rezafungin was generally well tolerated. IMPORTANCE Antifungal agents used to treat life-threatening infections are often associated with severe drug-drug interactions (DDIs) that may limit their usefulness. Rezafungin, a newly approved once-weekly echinocandin, has been shown to be free of DDIs based on extensive nonclinical and clinical testing described in this study.

Perampanel as first add-on antiseizure medication: Italian consensus clinical practice statements

BackgroundWhen use of a single antiseizure medication (ASM) fails to induce seizure remission, add-on therapy is justified. Perampanel (PER) is approved in Europe as adjunctive therapy for focal, focal to bilateral tonic-clonic seizures and generalized tonic-clonic seizures. Aim of the study was to establish whether PER is suitable for first add-on use.MethodsA Delphi methodology was adopted to assess consensus on a list of 39 statements produced by an Expert Board of 5 epileptologists. Using an iterative process, statements were finalized by a Delphi Panel of 84 Italian pediatric and adult neurologists. Each statement was rated anonymously to determine level of agreement on a 9-point Likert scale. Consensus was established as agreement by at least 80% of the panelists. The relevance of each statement was also assessed on a 3-point scale.ResultsConsensus was achieved for 37 statements. Characteristics of PER considered to justify its use as first add-on include evidence of a positive impact on quality of life based on long term retention data, efficacy, tolerability, and ease of use; no worsening of cognitive functions and sleep quality; a low potential for drug interactions; a unique mechanism of action. Potential unfavorable factors are the need for a relatively slow dose titration; the potential occurrence of behavioral adverse effects; lack of information on safety when used in pregnancy; limited access to plasma PER levels.ConclusionPerampanel has many features which justify its use as a first add-on. Choice of an ASM as first add-on should be tailored to individual characteristics.

Survey of Knowledge and Attitude of Pharmacists about Direct Oral Anticoagulants: A Cross-Sectional Study

Background: Direct oral anticoagulants (DOACs) are increasingly used due to fewer side effects, predictable pharmacokinetics, lower potential for drug interactions. Different levels of awareness among health care professionals have been reported.
 Methods: The main objectives of this study were to investigate the knowledge and attitude of pharmacists about direct oral anticoagulants. The present study was a descriptive cross-sectional study performed in Kermanshah province, Iran. The validated researcher-made questionnaire included questions about demographic characteristics and specialized questions that assessed the knowledge and attitude of pharmacists towards new oral anticoagulants. 
 Results: Out of 126 pharmacists participating in this study, 67 (53.2%) were male. The mean scores of knowledges and attitude in pharmacists were 64.94±5.84 and 28.62±3.98, respectively. The most common oral anticoagulant with a direct effect dispensed by pharmacists was rivaroxaban (77.4%). There was also a significant relationship between pharmacists' attitudes and their place of activity (P = 0.024).
 Conclusion: The results of this study showed that pharmacists had an acceptable knowledge and low attitude about DOACs.

Centella asiatica Water Extract Shows Low Potential for Cytochrome P450-Mediated Drug Interactions.

Centella asiatica (CA) shows considerable promise for development as a botanical drug for cognitive decline. Its primary bioactive components include triterpene glycosides asiaticoside and madecassoside and their corresponding aglycones asiatic acid and madecassic acid. Exploration of the bioactivity of CA's caffeoylquinic acids is ongoing. In this study, an aqueous extract of CA (CAW-R61J) was evaluated for drug interaction potential through inhibition or induction of P450 enzymes, as required by the US Food and Drug Administration. CAW-R61J was assessed for induction potential of CYP1A2, CYP2B6, and CYP3A4 using transporter-certified cryopreserved human hepatocytes in sandwich culture. Gene expression of these target P450s was quantified, and enzyme activities were determined to confirm gene expression results. No induction was observed up to 16.7 µg/ml CAW-R61J (equivalent to 1.1 µM asiaticoside, 0.8 µM madecassoside, 0.09 µM asiatic acid, and 0.12 µM madecassic acid). Reversible and time-dependent inhibitory effects of CAW-R61J on CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5 were evaluated using human liver microsomes. CAW-R61J showed weak reversible inhibition of most of the P450 forms tested, with the strongest being CYP2C9 (IC50 of 330 µg/ml). CAW-R61J (≤1000 µg/ml) was not a time-dependent inhibitor of any of these P450 enzymes. In summary, CAW-R61J had no, or only a weak impact, on P450 induction and inhibition in vitro. The clinical relevance of these results will depend on the in vivo concentration of CAW-R61J components achieved in humans. Plasma triterpene concentrations measured in our recent clinical studies suggest minimal risk of P450-mediated drug interactions by these components. SIGNIFICANCE STATEMENT: A preparation of Centella asiatica is currently under clinical development for the prevention or treatment of cognitive decline. The US Food and Drug Administration required an evaluation of its potential for drug interactions mediated through drug-metabolizing enzymes. This in vitro study revealed minimal induction or inhibition of a range of P450 enzymes, including CYP3A4, by the C. asiatica extract, suggesting a low potential for drug interactions modulated by P450 metabolism.

Statins and aspirin in the prevention of cardiovascular disease among HIV-positive patients between controversies and unmet needs: review of the literature and suggestions for a friendly use

BackgroundAs in non-infected subjects, statins and aspirin have a pivotal preventive role in reducing the cardiovascular related morbidity and mortality in HIV infected patients. The persistence of immune activation in these subjects, could contribute to accelerate atherosclerosis, therefore, these treatments that reduce inflammation could provide additional cardiovascular protection. However the current guidelines for the use of these drugs in general population are dissimilar, with important differences between American and European ones. Aim of the present position paper is to provide recommendations aimed to overcome the actual differences and limitations among the current ones and to adapt them to the needs of HIV infected patients.ResultsWe propose to adopt the new ACC/AHA guidelines, simple to use and cost effective, to use the ASCVD score that seems to estimate more accurately the cardiovascular risk among these patients. We suggest to start statin therapy in all patients with a calculated 10-year risk of a cardiovascular event of 10% or greater. Rosuvastatin and atorvastatin should be preferred. LDL-C target may be adopted. Aspirin should be always associated with a statin, in secondary prevention, while in primary prevention it should be reserved only to patients with ≥ 20% 10-year risk particularly adherent to treatments, and with low risk of bleeding. We suggest to start with a dose of 100 mg/day. Finally, management of antiplatelet agents or novel oral anticoagulants may include selecting antiretrovirals with a lower potential for drug interactions or choosing agents least likely to interact with antiretrovirals.ConclusionsAs demonstrated in surveys, HIV physicians are generally highly committed regarding CVD and autonomous in prescribing statins and ASA. Consequently, in the light of the previously discussed discrepancies among the different guidelines and of the incomplete indications regarding HIV-positive persons, the present suggestions could overcome the actual differences and limitations among the current ones.

Potential protein-binding displacement interactions with perampanel: An in vitro analysis

Plasma protein binding and effects on volume of distribution and pharmacologically active, circulating-drug concentrations are complex issues. Protein-binding displacement often underlies drug–drug interactions. Perampanel is a once-daily oral anti-seizure drug for focal seizures and primary generalized tonic-clonic seizures. Perampanel is also indicated for monotherapy use for focal seizures in the United States. Perampanel is extensively but slowly metabolized via CYP3A4. Its elimination t½ is about 100 h, and it displays substantial plasma protein binding (>95%). Here, we examine perampanel’s potential to displace highly bound anti-seizure drugs and the ability of warfarin, a standard highly protein-bound drug, to displace perampanel. Protein binding of perampanel, phenytoin, valproate, and warfarin was assessed using equilibrium dialysis. Plasma samples containing each compound were dialyzed against phosphate buffered saline. For phenytoin, valproate, and warfarin, plasma samples were also dialyzed in the presence of perampanel. After 24 h equilibrium dialysis, amounts of test compounds were analyzed to calculate plasma protein binding. At clinically relevant concentrations, perampanel did not displace other highly bound drugs or vice versa. Protein-binding displacement may confound therapeutic drug monitoring of extensively protein-bound medications. Without empirical data, clinicians might be concerned that addition of perampanel could alter unbound concentrations of other medications, resulting in adverse effects. Our data indicate perampanel has low potential for drug interactions resulting from protein-binding displacement.

Sodium zirconium cyclosilicate: a new potassium binder for the treatment of hyperkalemia.

Hyperkalemia is one of the most common electrolyte disturbances, especially among some groups of patients, such as in those with chronic kidney disease, diabetes or heart failure. Hyperkalemia has been associated with increased risks of mortality, arrhythmias, hospitalization and costs, as well as the need to down titrate/discontinue renin-angiotensin-aldosterone system inhibitors (RAASIs), despite their well-known cardiovascular and nephroprotective benefits. Current potassium binders have limitations (slow onset of action, limited selectivity for potassium binding, risk of drug interactions or gastrointestinal intolerance). Sodium zirconium cyclosilicate (SZC) is a new potassium binder recently approved for the treatment of chronic hyperkalemia. It is a nonabsorbable, inorganic crystal which selectively binds potassium and ammonium in exchange of Na+ and H+ in the whole gastrointestinal tract, achieving a rapid correction of serum potassium levels (within 2 days) and maintaining normokalemia in the long term (up to 1 year), with a good safety profile (common adverse reactions include gastrointestinal events and a dose-dependent risk of edema), excellent tolerability and a low potential for drug interactions. Its potassium-lowering efficacy is maintained irrespective of the use of RAASIs. In summary, SZC is a new potassium binder recently approved for the treatment of hyperkalemia. Its differences with respect to currently available potassium binders make SZC an attractive therapeutic option.

Brivaracetam: a novel antiepileptic drug for focal-onset seizures.

Brivaracetam (BRV), the n-propyl analogue of levetiracetam (LEV), is the latest antiepileptic drug (AED) to be licensed in Europe and the USA for the adjunctive treatment of focal-onset seizures with or without secondary generalization in patients aged 16 years or older. Like LEV, BRV binds to synaptic vesicle protein 2A (SV2A), but BRV has more selective binding and a 15- to 30-fold higher binding affinity than LEV. BRV is more effective than LEV in slowing synaptic vesicle mobilization and the two AEDs may act at different binding sites or interact with different conformational states of the SV2A protein. In animal models, BRV provides protection against focal and secondary generalized seizures and has significant anticonvulsant effects in genetic models of epilepsy. The drug undergoes first-order pharmacokinetics with an elimination half-life of 7–8 h. Although BRV is metabolized extensively, the main circulating compound is unchanged BRV. Around 95% of metabolites undergo renal elimination. No dose reduction is required in renal impairment, but it is recommended that the daily dose is reduced by one-third in hepatic dysfunction that may prolong half-life. BRV has a low potential for drug interactions. The efficacy and tolerability of adjunctive BRV in adults with focal-onset seizures have been explored in six randomized, placebo-controlled studies. These showed significant efficacy outcomes for doses of 50–200 mg/day. The most common adverse events reported were headache, somnolence, dizziness, fatigue and nausea. Patients who develop psychiatric symptoms with LEV appear to be at risk of similar side effects with BRV, although preliminary data suggest that these issues are likely to be less frequent and perhaps less severe. As with all AEDs, a low starting dose and slow titration schedule help to minimize side effects and optimize seizure control and thereby quality of life.

Antiepileptic Drug Treatment in Community-Dwelling Older Patients with Epilepsy: A Retrospective Observational Study of Old- Versus New-Generation Antiepileptic Drugs.

The use of antiepileptic drugs (AEDs) in older patients with epilepsy is challenged by polypharmacy and decreased drug elimination. Newer AEDs have a lower potential for drug interactions and are reported to be better tolerated by the elderly than old-generation AEDs. The objective of this study was to evaluate AED use and the related adverse event rate in an outpatient cohort of older patients with epilepsy. We retrospectively reviewed the computerized database and medical records of all the patients aged ≥60years who visited our epilepsy outpatient clinic (Assaf Harofeh Medical Center, Zerifin, Israel) during a 4-year period from February 2012 to February 2016. In this study, phenytoin, valproic acid, carbamazepine, phenobarbital, clobazam, and clonazepam were defined as old-generation AEDs. Gabapentin, levetiracetam, lamotrigine, topiramate, oxcarbazepine, lacosamide, and perampanel were defined as new-generation AEDs. The study group included 115 patients aged 60-90years (mean 70.5±7.8years), 70 (61%) of whom were men. Co-morbidities were present in 98.3% of the patients, including neuropsychiatric illnesses in 21.2%. Present medical treatment included new-generation AEDs in 49 (44.5%) and both old- and new-generation AEDs in 20 (18.2%) patients. The most commonly used current AEDs were phenytoin, gabapentin, levetiracetam, and lamotrigine. Adverse reactions mainly included fatigue and CNS-related symptoms, and were more frequent among patients treated with new-generation AEDs than in those treated with old-generation AEDs or a combination of old- and new-generation AEDs; however, these reactions were mostly related to levetiracetam treatment. The likelihood of levetiracetam-related adverse events was increased by slow levetiracetam titration [defined as a weekly dose increase of ≤250mg/day in this study; odds ratio (OR) 16.35, 95% confidence interval (CI) 2.94-90.98], and by low- (OR 5.68, 95% CI 1.40-22.95) and high (OR 4.24, 95% CI 1.28-14.02) levetiracetam dosages compared with patients treated with lamotrigine or gabapentin. New-generation AEDs were administered to most of the patients in this outpatient clinic-based cohort of older patients with epilepsy. In order to decrease levetiracetam-related adverse events in this age group, we suggest that a slower titration rate (e.g., an increase of ≤125mg/day each week) and lower maximal dosage (e.g., 1500mg/day) of the drug should be considered.

Pharmacological indices and pulmonary distribution of rifampicin after repeated oral administration in healthy foals.

The treatment of equine lung infections by Rhodococcus equi with rifampicin is empirically based because pharmacokinetic/pharmacodynamic (PK/PD) indices and pivotal clinical outcome data are not available. To evaluate the pharmacokinetics and pulmonary distribution of rifampicin into epithelial lining fluid (ELF) and bronchoalveolar lavage cells (BALC) to predict antimicrobial activity in the lung using PK/PD indices. Controlled, randomised, two-period, crossover, repeated-dose study with an initial arm to measure disposition after i.v. administration of rifampicin. Pharmacokinetics and lung distribution were evaluated in six healthy foals treated with 10 mg/kg bwt rifampicin i.v. (initial arm) and with repeated oral doses of rifampicin at 10 mg/kg bwt and 20 mg/kg bwt once per day for 10 days (crossover arms). ELF and BALC were sampled by bronchoalveolar lavage 24 h after the last oral dosing. Rifampicin and 25-O-desacetyl rifampicin were quantified using liquid chromatography tandem-mass spectrometry. Enzyme induction by rifampicin was confirmed by evaluation of plasma 4β-OH-cholesterol:cholesterol ratios. The distribution volume of rifampicin administered i.v. was ~0.85 L/kg. Terminal elimination half-life was ~11 h. Orally given rifampicin was slowly absorbed (Tmax , range: 2.5-8.0 h) and eliminated with apparent half-lives of ~6-8 h. Trough concentrations in ELF and BALC were 1.01 ± 0.20 μg/mL and 1.25 ± 0.29 μg/mL, respectively, after 10 mg/kg bwt rifampicin and 2.71 ± 1.25 μg/mL and 3.09 ± 1.63 μg/mL, respectively, after 20 mg/kg bwt rifampicin. The average ratios of area under the plasma concentration time curve during an administration interval of 24 h (AUC0-24 h ) to minimum inhibitory concentration (MIC) were 145 and 322 h, respectively, for less susceptible strains of R. equi (MIC90 : 0.5 μg/mL). The clearance and bioavailability of rifampicin after repeated oral dosing were not evaluated. Treatment with rifampicin at 10 mg/kg bwt administered once per day is suitable to generate drug concentrations above the MIC90 in the ELF and BALC of foals. Future clinical studies with rifampicin in combination with macrolide antibiotics with low drug interaction potential are required to translate the PK/PD indices into protocols for the treatment of R. equi lung infections.

Clinical Pharmacokinetics of Ombitasvir.

Ombitasvir is a potent, nonstructural protein 5A inhibitor of the hepatitis C virus (HCV) that is used in combination with other direct-acting antivirals for the treatment of chronic HCV infection. Ombitasvir is predominantly metabolized by amide hydrolysis followed by oxidative metabolism and is a substrate of P-glycoprotein. Ombitasvir displays linear pharmacokinetics with minimal accumulation and is eliminated via metabolism and biliary excretion. A negligible amount of unchanged drug is excreted in urine. Exposures are comparable across Chinese, Japanese, and non-Asian subjects. The pharmacokinetic characteristics of ombitasvir are similar in healthy subjects and HCV-infected patients, and are not appreciably altered by hepatic or renal impairment. Results from several drug interaction studies demonstrated that ombitasvir has a low potential for drug interactions.

Dalbavancin for the treatment of paediatric infectious diseases.

To review the topics of interest related to the use of dalbavancin in paediatric patients. PubMed was used to search for all of the studies published over the last 15years using the key word "dalbavancin". A total of 36 manuscripts were selected, and due to the limited pediatric experience a further research was performed in order to identify clinical trials ongoing. Three studies that concerned children were found in clinicaltrials.gov. This review considers also the manuscripts published on the adult population in order to highlight the gaps requiring further research at pediatric age. Dalbavancin has emerged as a promising agent against resistant Gram-positive invasive infections. It is approved in the United States and Europe for the treatment of adult patients with acute bacterial skin and skin structure infections (SSTIs). Compared to other available antibiotics that are active against multi-resistant bacteria, the advantages of dalbavancin include a lower potential for drug interactions and the possibility of fewer required doses due to a longer half-life. Pharmacokinetic characteristics of dalbavacin are attractive for its clinical impact, especially for children who may avoid prolonged hospitalization and central venous access. However, further studies are needed to establish its appropriate paediatric dosage before it can be licensed for use in newborns and children. For younger patients, at a time when infections due to multidrug-resistant Gram-positive pathogens are increasing, dosage, efficacy and safety data for dalbavancin are needed to ensure the highest antimicrobial efficacy while also minimizing the risk of adverse events.

Continuous manufacturing of delta mannitol by cospray drying with PVP

Mannitol is a frequently used diluent in the production of tablets due to its non-hygroscopic character and low drug interaction potential. Although the δ-polymorph of mannitol has superior tabletability in comparison to α- and β-mannitol, the latter are most commonly used because large-scale production of δ-mannitol is difficult. Therefore, a continuous method for production of δ-mannitol was developed in the current study. Spray drying an aqueous solution of mannitol and PVP in a ratio of 4:1 resulted in formation of δ-mannitol. The tabletability of a physical mixture of spray dried δ-mannitol with PVP (5%) and paracetamol (75%) was clearly superior to the tabletability of physical mixtures consisting of spray dried α- and β-mannitol with PVP (5%) and paracetamol (75%) which confirmed the excellent tableting properties of the δ-polymorph. In addition, a coprocessing method was applied to coat paracetamol crystals with δ-mannitol and PVP. The tabletability of the resulting coprocessed particles consisting of 5% PVP, 20% δ-mannitol and 75% paracetamol reached a maximal tensile strength of 2.1MPa at a main compression pressure of 260MPa. Moreover the friability of tablets compressed at 184MPa was only 0.5%. This was attributed to the excellent compression properties of δ-mannitol and the coating of paracetamol crystals with δ-mannitol and PVP during coprocessing.

Daclatasvir in hepatitis C virus infection: a guide to its use in the EU

Daclatasvir (Daklinza®), an inhibitor of hepatitis C virus (HCV) NS5A protein, is an oral, direct-acting antiviral with potent pangenotypic activity that approved in many countries worldwide. In the EU, it is approved for use in combination with other drugs for the treatment of chronic HCV genotype 1, 3 or 4 infection. Daclatasvir produces high sustained virological response rates in patients chronically infected with HCV genotypes 1–4 when used in combination with peginterferon-α + ribavirin or in combination with sofosbuvir (± ribavirin). Daclatasvir has a moderately high genetic barrier to resistance, is effective during short-term treatment over 12 weeks, has a safety and tolerability profile similar to that of placebo, has a relatively low potential for drug interactions, and is not associated with clinically relevant drug interactions with drugs commonly used in patients with HCV, including other antivirals and transplant medications.

Is Coenzyme Q10 Effective in Protection against Ulcerative Colitis? An Experimental Study in Rats.

Coenzyme Q10 (Co-Q10) is a vitamin-like supplement which appears to be safe, with minimal side effects and low drug interaction potential. Co-Q10 is used in the treatment of a variety of disorders related primarily to suboptimal cellular energy metabolism and oxidative injury. Studies supporting the efficacy of Co-Q10 appear most promising for a variety of diseases, including ulcerative colitis (UC). The present investigation aims to elucidate the possible protective effects of Co-Q10 against UC, as induced by the administration of iodoacetamide to adult male albino rats. In our study, Co-Q10 showed potent anti-oxidant and anti-inflammatory activities through a significant increase in catalase activity and glutathione content. In addition, it significantly decreased myeloperoxidase activity, malondialdehyde content and nitrate/nitrite production. These results suggest that Co-Q10 protects against UC in rats via anti-oxidant and anti-inflammatory potentials, and therefore seems promising for use in further clinical trials.

Mecanismo de acción, farmacología e interacciones de dolutegravir

Dolutegravir is a second-generation integrase strand transfer inhibitor (INSTI), whose potential and binding half-life in the integrase are far superior to those of raltegravir and elvitegravir, conferring it with unique characteristics in terms of its genetic barrier to resistance and activity against viruses with one or more mutations in the integrase. The pharmacokinetic properties of dolutegravir allow once-daily dosing (50 mg), with or without food, maintaining concentrations far above those effective against wild-type viruses. If integrase resistance mutations are present, the recommended dosing regimen is 50 mg/12 h. The distribution of dolutegravir in cerebrospinal fluid is good and effective concentrations are also reached in the male and female genital tracts. Dolutegravir is metabolized by UGT1A1 and, to a lesser extent, by CYP3A4, without being an inducer or inhibitor of the usual metabolic systems. It has a very low potential for drug interactions and can be administered in routine doses with most drugs. Dose adjustment is not required, even in patients with renal insufficiency or mild or moderate liver failure. Increasing the dose of dolutegravir (50 mg/12 h) is only recommended when administered with efavirenz, nevirapine, fosamprenavir/r, tipranavir/r, rifampicin, carbamazepine, phenytoin and phenobarbital. Coadministration of dolutegravir with etravirine is not recommended without a protease inhibitor or with Hypericum perforatum. Dolutegravir should be administered 2 h before or 6 h after antacids or products with polyvalent cations. Dolutegravir can reduce renal tubule secretion of substances excreted via OCT2, with a slight initial increase in creatinine, with no risk of renal toxicity. The drug can also increase metformin concentrations and consequently monitoring is recommended in case dose adjustment is required. In summary, dolutegravir has excellent pharmacokinetic and drug interaction profiles.

Combination dolutegravir-abacavir-lamivudine in the management of HIV/AIDS: clinical utility and patient considerations.

The current standard of care for human immunodeficiency virus (HIV) treatment is a three-drug regimen containing a nonnucleoside reverse transcriptase inhibitor, a protease inhibitor, or an integrase strand transfer inhibitor (INSTI) plus two nucleoside/tide reverse transcriptase inhibitors. Given their potency, safety, and distinctive mechanism of action, INSTIs represent an important advance in HIV type 1 (HIV-1) therapy. Dolutegravir (DTG) is a new-generation INSTI recently approved for the treatment of HIV-1-infected adult patients, with distinct advantages compared with other available antiretroviral agents. In well-designed, large clinical trials, DTG-containing regimens have demonstrated either noninferiority or superiority to current first-line agents such as raltegravir-, darunavir/ritonavir-, and efavirenz-containing regimens. The favorable safety profile, low potential for drug interactions, minimal impact on lipids, good tolerability, and high resistance barrier of DTG makes this compound one of the preferred choices for HIV therapy in multiple clinical scenarios, including treatment-naïve and treatment-experienced patients. DTG is the only antiretroviral drug not yet associated with de novo emergence of resistance mutations in treatment-naïve individuals. However, data from in vitro studies and clinical trial suggest the possibility of cross-resistance between first- and second-generation INSTIs. Even though these profiles are infrequent at the moment, they need to be monitored in all current patients treated with INSTIs. With its potent activity, good tolerability, simplicity of dosing, and minimal drug interaction profile, DTG will likely play a major role in the management of patients with HIV-1 infection. On the basis of clinical trial data, current guidelines endorse DTG in combination with nucleoside/tide reverse transcriptase inhibitors as one of the recommended regimens in antiretroviral therapy-naïve patients. Most of the favorable clinical experiences from clinical trials are based on the combination of DTG with abacavir/lamivudine, and DTG is planned to be coformulated with abacavir/lamivudine. This will provide a further advantage, given that single tablet regimens are associated with higher adherence rates as well as improvement in quality of life and enhanced patient preference.

Fidaxomicin: A Novel Macrolide Antibiotic for <I>Clostridium difficile</I> Infection

To review the chemistry, pharmacology, microbiology, pharmacodynamics, pharmacokinetics, clinical efficacy, tolerability, drug interactions, dosing, and administration of fidaxomicin (FDX). A search of PubMed using the terms "fidaxomicin," "OPT-80," "PAR-101," "OP-1118," "difimicin," "tiacumicin," and "lipiarmycin" was performed. All English-language articles from 1983 to November 2013 were reviewed for relevance. Bibliographies of all articles were reviewed as well as the manufacturer's Web site to further identify relevant information. All English-language articles from 1983 to November 2013 appearing in these searches were reviewed for relevance to this paper. In addition, their bibliographies were reviewed to identify any articles not identified in the searches. FDX is the first macrolide antibiotic with a narrow spectrum of activity targeted against Clostridium difficile. It is administered orally without regard to food. The primary route of elimination is fecal excretion. Advanced age, hepatic dysfunction, or renal impairment do not alter its disposition. Phase III clinical trials have demonstrated that FDX 200 mg twice daily for 10 days is noninferior to vancomycin 125 mg four times daily for 10 days in the treatment of adults with C. difficile infection and is associated with lower recurrence rates. FDX has a favorable side effect profile and a low potential for drug interactions. FDX has been shown to be safe and effective in the treatment of adults with C. difficile infection. Further research and pharmacoeconomic studies are needed to clarify and refine its role in the treatment of patients at high risk for recurrence.

The role of carbonyl reducing enzymes in oxcarbazepine in vitro metabolism in man

Oxcarbazepine, a second generation antiepileptic drug belonging to the family of dibenz[b,f]azepines, is subjected to a rapid and extensive biotransformation. Oxcarbazepine demonstrates a low potential for drug interactions because its biotransformation is mainly mediated by the reduction pathway instead of oxidative pathways, which are very susceptible to drug interactions. The reductive metabolism of oxcarbazepine yields a 10-monohydroxy derivative (10,11-dihydro-10-hydroxy-carbazepine), which is responsible for the pharmacological activity. The identity and localization of enzymes participating in the reduction of oxcarbazepine in response to this active metabolite have remained unknown until now. Thus, we investigated the reductive metabolism of oxcarbazepine in human liver subcellular fractions and using recombinant carbonyl reducing enzymes. The reduction of oxcarbazepine was shown to occur largely in the liver cytosol rather than liver microsomes. Furthermore, the activity and stereospecificity of cytosolic carbonyl reducing enzymes toward oxcarbazepine were assessed. Of the eight tested enzymes, six reductases were identified to contribute to the reduction of oxcarbazepine. The highest activities were demonstrated by AKR1C1, AKR1C2, AKR1C3, and AKR1C4. The contribution of CBR1 and CBR3 to the reduction of oxcarbazepine was also significant, although their role in oxcarbazepine metabolism in vivo is unclear.

Cobicistat: a guide to its use as a pharmacokinetic enhancer of atazanavir and darunavir in HIV-1 infection

Oral cobicistat (Tybost™), a selective CYP3A inhibitor without intrinsic anti-HIV activity, is an emerging alternative to ritonavir for the pharmacokinetic enhancement of protease inhibitors (PIs) in adults with HIV-1 infection. Relative to low-dose ritonavir, cobicistat has a lower potential for drug interactions, provides bioequivalent PI exposure, is associated with noninferior virological suppression rates, has a similar tolerability profile and is more soluble, making co-formulation with antiretroviral drugs easier.