3A4 Isoenzyme Research Articles

A Case of Suicidal Thoughts With Alprazolam

To the Editor: This is the first report, to our knowledge, of suicidal thoughts emerging after a dose of alprazolam. Case report. Ms A, a woman in her late 20s, presented for the first time in 2008 and was diagnosed with obsessive-compulsive disorder with panic attacks (DSM-IV criteria) and was prescribed fluoxetine 20 mg in the morning and alprazolam 0.25 mg 3 times a day as needed. She was not depressed and had not experienced suicidal thoughts in the past. After a single dose of both alprazolam 0.25 mg and fluoxetine 20 mg, she experienced grogginess and sleepiness that lasted for 24 hours. She continued taking only fluoxetine for the next 2 weeks without any side effects. However, as she still experienced panic-like symptoms, she tried taking half the initial dose of alprazolam (half a tablet of alprazolam 0.25 mg) together with fluoxetine 20 mg. This time, she described the “grogginess and sleepiness” as less severe than the first time with alprazolam 0.25 mg. The next morning, she repeated the same doses of alprazolam with fluoxetine and reported “feeling worse in a different way.” She had thoughts of jumping down from her apartment. These thoughts lasted “till the effects wore off,” referring to the grogginess and sleepiness. Subsequent to this, she has stopped taking alprazolam completely and continued with fluoxetine without experiencing similar symptoms. The product literature on alprazolam does not report suicidal thoughts or ideation.1 A meta-analysis of controlled trials of alprazolam in treatment of depression does not suggest that alprazolam is associated with increased risk of suicidality.2 The majority of those treated with alprazolam experienced improvement of suicidal ideation, and that rate of improvement was significantly greater for those taking alprazolam compared to those taking placebo (71.9% vs 57.7%). However, there are reports indicating that all benzodiazepines have been associated with the emergence or worsening of depression3,4; whether they were causative is unknown. Benzodiazepines have also been observed to precipitate suicide in already depressed patients.5 The American Psychiatric Association report on benzodiazepines warns, in discussing toxicity, that benzodiazepines have been reported to cause or exacerbate symptoms of depression. This is not a frequent side effect, but depressive symptoms can be potentially serious.6 The United Kingdom's Committee on Safety of Medicines recommends that benzodiazepines should not be used alone to treat depression or anxiety associated with depression. Suicide may be precipitated in such patients.7 In another report,8 there were 6 patients, previously emotionally stable, who experienced suicidal ideation with a cluster of other symptoms; however, all of these patients had taken greater than maximally recommended doses of diazepam (above 40 mg a day) primarily for medical conditions.8 Coadministered fluoxetine can increase serum alprazolam concentrations.9,10 The interaction effect is an increased risk of alprazolam toxicity with symptoms such as somnolence, dizziness, ataxia, slurred speech, hypotension, and psychomotor impairment. In the study by Greenblatt et al,9 12 healthy male volunteers were given fluoxetine 20 mg twice a day or placebo and a single dose of alprazolam 1 mg on days 3 and 24 of the 31-day, double-blind, crossover study. Fluoxetine significantly increased the half-life of alprazolam from 17 hours to 20 hours and significantly decreased its clearance from 61 mL/min to 48 mL/min. The mechanism of action is thought to be through inhibition of the cytochrome P450 3A4 isoenzyme, which is responsible for alprazolam metabolism. Whether alprazolam actually triggered the suicidal thoughts or whether these were in relation to the side effects this patient experienced cannot be clearly determined. However, there is high probability, given the risks associated with benzodiazepine use, that alprazolam contributed to the emergence of suicidal thoughts in this patient. The combination of fluoxetine with alprazolam should be used with caution in patients with anxiety disorders.

Excessive Neurotoxicity With ABVD When Combined With Protease Inhibitor–Based Antiretroviral Therapy in the Treatment of AIDS-Related Hodgkin Lymphoma

Hodgkin lymphoma (HL) is the second most common non-AIDS-defining malignancy among persons infected with HIV, and its incidence might be increasing in the current era of combination antiretroviral therapy (cART). With the immune reconstitution afforded by cART, most patients are now able to tolerate the standard-dose chemotherapies administered to immunocompetent individuals with HL, such as ABVD (doxorubicin/bleomycin/vinblastine/dacarbazine). Antiretroviral therapy is commonly prescribed concomitantly with chemotherapy in the treatment of AIDS-related malignancies. However, little is known about the pharmacokinetic consequences of combined therapy. In particular, the potential for excessive vinca alkaloid-associated toxicity is significant, given the metabolism of drugs such as vinblastine by the 3A4 isoenzyme of the cytochrome P450 system and the inhibition of this isoenzyme by protease inhibitors. We report 3 patients who experienced severe vinblastine-associated neurotoxicity during concomitant treatment with ritonavirboosted antiretrovirals. The implications for the treatment of patients with HL in the current era of cART are discussed.

Rhabdomyolysis following co-prescription of fusidic acid and atorvastatin

The placebo-corrected incidence of rhabdomyolysis in a systematic review of 20 statin trials was 1.6/100,000 per year. It is likely to be higher than this in everyday clinical practice when statins are knowingly or inadvertently co-prescribed with drugs that interfere with their metabolism. We report a case of rhabdomyolysis causing muscle weakness and prolonging an episode of dialysis-dependent acute kidney injury, which occurred when fusidic acid was co-prescribed with atorvastatin. Renal function and muscle power recovered when both drugs were withdrawn. We found four other cases of rhabdomyolysis with fusidic acid and atorvastatin and three with fusidic acid and simvastatin in the literature, a review of which suggests that the risks of rhabdomyolysis vary with the extent to which an individual statin is dependent for its metabolism on the cytochrome P450 3A4 isoenzyme and the degree to which this isoenzyme's activity is inhibited by a particular antimicrobial. Of note, the interaction between statins and fusidic acid did not feature in seven of eight recent reviews of statin toxicity. Our case report highlights the importance of close monitoring of patients on statins, especially when new drugs are started or if patients become unwell, by checking creatine kinase and liver function tests and by examining for new muscle weakness. Our review of statin-antimicrobial drug interactions suggests that fusidic acid is another CYP450 3A4 enzyme inhibitor with the potential to cause rhabdomyolysis when co-prescribed with simvastatin and atorvastatin.

Understanding the Genetic Basis for Adverse Drug Effects: The Calcineurin Inhibitors

The calcineurin inhibitors-cyclosporine and tacrolimus-are the mainstay of immunosuppressive therapy in solid organ transplantation. These drugs produce severe adverse drug effects (ADEs) such as nephrotoxicity, posttransplantation diabetes mellitus, and hypertension. Accumulated evidence suggests that the development of type 2 diabetes, hypertension, and renal failure may be associated with specific DNA genotypes. In this review, the genes involved with the development of these disease processes are compared with those implicated in calcineurin inhibitor-induced ADEs. The renin-angiotensin system genes, cytokine-encoding genes, and plasminogen activator inhibitor type 1 genes have been implicated in calcineurin inhibitor-induced nephrotoxicity, as well as in development of renal failure. A number of genes are implicated in contributing to diabetes, and these include the vitamin D receptor gene, VDR; hepatocyte nuclear factor genes, HNF; transcription factor 7-like 2 gene, TCF7L2; angiotensin-converting enzyme gene, ACE; cytokines; peroxisome proliferator-activated receptor gamma gene, PPARG; and others. Studies have suggested that the VDR, PPARG, HNF1A, and adenosine 5'-triphosphate-binding cassette ABCC8 (which encodes the sulfonylurea receptor) genes are associated with calcineurin inhibitor-induced diabetes. The genes encoding for the angiotensin-converting enzyme, endothelial constitutive nitric oxide synthase, and cytochrome P450 3A isoenzyme have been involved in the development of hypertension and in calcineurin inhibitor-induced hypertension. The genetic study of disease states can be the stepping stones for thoroughly understanding the genetic basis of ADEs. Gene polymorphisms are implicated in the development of diseases and corresponding disease-like ADEs. The disease-associated genes provide candidate genes for exploring ADEs and may provide genomic biomarkers for assessing the risk for developing severe calcineurin inhibitor-related ADEs as well as for developing preventive strategies.

Pharmacokinetic interaction between oral lovastatin and verapamil in healthy subjects: role of P-glycoprotein inhibition by lovastatin

Lovastatin is an inhibitor of P-glycoprotein (P-gp) and is metabolized by the cytochrome P450 (CYP) 3A4 isoenzyme. Verapamil is a substrate of both P-gp and CYP3A4. It is therefore likely that lovastatin can alter the absorption and metabolism of verapamil. The pharmacokinetic parameters of verapamil and one of its metabolites, norverapamil, were compared in 14 healthy male Korean volunteers (age range 22-28 years) who had been administered verapamil (60 mg) orally in the presence or absence of oral lovastatin (20 mg). The design of the experiment was a standard 2 x 2 crossover model in random order. The pharmacokinetic parameters of verapamil were significantly altered by the co-administration of lovastatin compared to the control. The area under the plasma concentration-time curve (AUC (0-infinity)) and the peak plasma concentration of verapamil were significantly increased by 62.8 and 32.1%, respectively. Consequently, the relative bioavailability of verapamil was also significantly increased (by 76.5%). The (AUC (0-infinity)) of norverapamil and the terminal half-life of verapamil did not significantly changed with lovastatin coadministration. The metabolite-parent ratio was significantly reduced (29.2%) in the presence of lovastatin. Lovastatin increased the absorption of verapamil by inhibiting P-gp and inhibited the first-pass metabolism of verapamil by inhibiting CYP3A4 in the intestine and/or liver in humans.

Tacrolimus use in adult allogeneic stem cell transplant recipients receiving voriconazole: preemptive dose modification and therapeutic drug monitoring

Concomitant use of tacrolimus and voriconazole, both competitive inhibitors of the CYP450 3A4 isoenzyme, requires tacrolimus dose reduction. On the basis of clinical observations, we developed a preemptive dose-reduction strategy in allograft recipients who received voriconazole to maintain tacrolimus concentrations within a target range. A total of 27 patients started i.v. tacrolimus at an average daily dose of 0.022 mg/kg on day -1 (30% lesser than the usual starting dose). The dose was reduced by 30-40% if the 48-h steady-state concentration was 7-10 ng/ml, and by 40-50% if it was 10-15 ng/ml. No change was made if the concentration was <7 ng/ml. Subsequently, concentrations were generally monitored 2-3 times a week with dose adjustments as necessary. None of the 170 levels (3-12 per patient; median 5) obtained between days +1 and +16 were subtherapeutic (<5 ng/ml) and only 34 levels (20%) were >15 ng/ml. Each patient required dose reduction at least twice. The dose had to be increased in only two patients after the initial dose reduction. The median tacrolimus doses in mg/kg declined with time; being 0.022, 0.008 and 0.006 on days 0, 7 and 14, respectively. We conclude that a preemptive dose-reduction strategy is effective in maintaining tacrolimus concentrations within the desired therapeutic range, although serial monitoring remains prudent.

Perazine at therapeutic drug concentrations inhibits human cytochrome P450 isoenzyme 1A2 (CYP1A2) and caffeine metabolism – an in vitro study

The aim of the present study was to estimate the inhibitory effect of perazine, a phenothiazine neuroleptic with piperazine structure in a side chain, on human CYP1A2 activity measured as a rate of caffeine 3-N- and 1-N-demethylation. Moreover, the influence of perazine on other caffeine metabolic pathways such as 7-N-demethylation (CYP1A2, CYP2C8/9, CYP3A4) and 8-hydroxylation (CYP3A4, CYP1A2, CYP2C8/9) was also determined. The Dixon analysis showed that in both human liver microsomes and Supersomes CYP1A2 perazine potently and to a similar degree inhibited caffeine 3-N-demethylation (Ki=3.5μM) and 1-N-demethylation (Ki=5μM). Perazine moderately diminished the rate of caffeine 7-N-demethylation in Supersomes CYP1A2 (Ki=11.5μM) and liver microsomes (Ki=20μM), and attenuated C-8-hydroxylation (Ki=15.5μM) in Supersomes CYP1A2. On the other hand, perazine weakly inhibited caffeine C-8-hydroxylation in liver microsomes (Ki=98μM). About 80% of basal CYP1A2 activity was reduced by the therapeutic concentrations of perazine (5–10μM).The obtained results show that perazine at its therapeutic concentrations is a potent inhibitor of human CYP1A2. Hence, taking account of CYP1A2 contribution to the metabolism of endogenous substances (steroids), drugs (xanthine derivatives, phenacetin, propranolol, imipramine, phenothiazine neuroleptics, clozapine) and carcinogenic compounds, the inhibition of CYP1A2 by perazine may be of physiological, pharmacological and toxicological importance.

Losartan Metabolite EXP3179

Losartan potassium, the first orally active nonpeptide angiotensin receptor blocker (ARB) to be introduced for clinical use in hypertension, is rapidly absorbed after oral administration, reaching a peak in plasma 1 to 2 hours. Despite being metabolized by the cytochrome P450 (CYP) 3A4, 2C9, and 2C10 isoenzymes, losartan has no clinically relevant interactions with inhibitors and stimulators of the CYP450 system and, like the other ARBs, is devoid of significant adverse effects: hypotension-related dizziness was the only drug-related event reported more frequently with losartan monotherapy than with placebo in clinical trials.1 After oral administration about 14% of a losartan dose is converted to the EXP3174 metabolite, which is 10- to 40-fold more potent than losartan and mediates most of its angiotensin type 1 receptor (AT1-R)–blocking effects. Losartan was generally deemed to be devoid of agonistic properties,2 but an important intermediate aldehyde metabolite EXP3179 has been identified (Figure).3 EXP3179 has no AT1-R–blocking activity, but potently inhibits the expression of endothelial cyclooxygenase (COX)-2, thereby exerting potent antiinflammatory actions. It also blocked intercellular adhesion molecule (ICAM)-1 mRNA upregulation and COX-dependent thromboxane A2 and prostaglandine F2α generation in vitro. Moreover, EXP3179 stimulated the phosphorylation of the endothelial nitric oxide synthase through a PI3-kinase/Akt pathway downstream of the VEGF-receptor 2 in cultured endothelial cells.4 As the ligand-activated PPAR-γ also exerts antiinflammatory actions (by inhibiting the action of proinflammatory transcription factors, such as AP-1 and nuclear factor kB), and represses COX-2 promoter activity and mRNA expression (by interacting with the c-jun component of the AP-1 complex), in this issue of Hypertension Kappert et al investigated the hypothesis that EXP3179-mediated activation of PPAR-γ entails a novel mechanism of the antiinflammatory antidiabetic actions of losartan.5 Figure. Schematic representation of losartan metabolism via cytochrome P450. See text for explanation. PPAR-γ is a nuclear …

Plasma levels and cerebrospinal fluid penetration by duloxetine in a patient with a non-fatal overdose during a suicide attempt

Duloxetine is a potent and selective inhibitor of serotonin and norepinephrine reuptake with weak activity on dopamine reuptake (Wong et al. 1993). Daily doses of 60 mg are effective in the acute treatment of major depression. Duloxetine is extensively metabolized by cytochrome P450 isoenzymes (CYP) 1A2 and to a lesser extent 2D6 (Lobo et al. 2008) to numerous non-active metabolites. Maximum plasma concentration occurs after 6 h, steady-state within 3 d and the mean terminal half-life is 12 h. Fatal outcomes have been reported for acute overdoses as low as 1000 mg, and symptoms of duloxetine overdose are well described. However, information about plasma levels of duloxetine and corresponding cerebrospinal fluid (CSF) levels providing information about its CSF penetration is lacking. We therefore report …

Maraviroc: A coreceptor CCR5 antagonist for management of HIV infection

The mechanism of action, pharmacology, pharmacokinetics, clinical efficacy, drug interactions, adverse effects, dosage and administration, cost, and role in therapy of maraviroc are reviewed. Maraviroc is the first CCR5 coreceptor antagonist to receive marketing approval from the Food and Drug Administration (FDA) for the treatment of CCR5-tropic human immunodeficiency virus (HIV) infection as part of an optimized antiretroviral regimen in treatment-experienced patients. As 50% or more of treatment-experienced patients may be infected with CXCR4-tropic virus, a tropism assay should be performed before initiating maraviroc therapy. The majority of evidence supporting maraviroc's use comes from two studies of HIV-infected, treatment-experienced patients. Pooled analysis from these two studies revealed that twice-daily maraviroc decreased HIV-1 RNA by 1.84 log copies/mL, compared with 0.78 log copy/mL with placebo. Forty-six percent of subjects attained an HIV-1 RNA concentration of <50 copies/mL, compared with only 17% with placebo. In a trial of treatment-naive HIV-infected individuals, maraviroc failed to show noninferiority to efavirenz. Maraviroc is metabolized by cytochrome P-450 isoenzyme 3A4 and is subject to interactions with inhibitors and inducers of that isoenzyme, such as the protease inhibitors (except tipranavir), efavirenz, and rifampin. Resistance has been reported with maraviroc, but specific mechanisms are still poorly understood. The most common adverse effects reported with maraviroc were diarrhea, nausea, fatigue, and headache. Available data support the use of maraviroc, the first CCR5 antagonist to receive FDA marketing approval, as part of an optimized antiretroviral regimen in treatment-experienced patients infected with CCR5-tropic HIV.

Unexpected Hepatotoxicity of Rifampin and Saquinavir/Ritonavir in Healthy Male Volunteers

ObjectivesRifampin is a potent inducer of the cytochrome P450 3A4 isoenzyme (CYP3A4) that metabolizes most protease inhibitor (PI) antiretrovirals. This study was designed to evaluate the steady-state pharmacokinetics and tolerability of the coadministration of the PIs saquinavir and ritonavir (a CYP3A4 inhibitor used as a pharmacoenhancer of other PIs) and rifampin when coadministered in healthy HIV-negative volunteers.MethodsIn an open-label, randomized, one sequence, two-period crossover study involving 28 healthy HIV-negative volunteers, arm 1 was randomized to receive saquinavir/ritonavir 1000/100 mg twice daily while arm 2 received rifampin 600 mg once daily for 14 days. Both arms were then to receive concomitant saquinavir/ritonavir and rifampin for 2 additional weeks. Vital signs, electrocardiography, laboratory analyses, and blood levels of total saquinavir, ritonavir, rifampin, and desacetyl-rifampin, the primary metabolite of rifampin, were measured.ResultsIn arm 1, 10/14 (71%) and, in arm 2, 11/14 (79%) participants completed the first study phase; eight participants in arm 1 and nine in arm 2 went on to receive both saquinavir/ritonavir and rifampin. Following substantial elevations (≥ grade 2) in hepatic transaminases in participants receiving the coadministered agents, the study was discontinued prematurely. Two participants in arm 1 displayed moderate elevations after five and four doses of rifampin, respectively. In arm 2, all participants experienced severe elevations within 4 days of initiating saquinavir/ritonavir. Clinical symptoms (e.g., nausea, vomiting, abdominal pain, and headache) were more common and severe in arm 2. Clinical symptoms abated and transaminases normalized following drug discontinuation. Limited pharmacokinetic data suggest a possible relationship between transaminase elevation and elevated rifampin and desacetyl-rifampin concentrations.ConclusionsAlthough not confirmed in HIV-infected patients, the data indicate that rifampin should not be coadministered with saquinavir/ritonavir.

Severe synergistic toxicity from docetaxel in a patient treated concurrently with protease inhibitors as part of HIV post-exposure prophylaxis: a case report

IntroductionDocetaxel is a semisynthetic taxane commonly used in solid tumour oncology. Its pharmacokinetics has been widely studied, and it is well established that it is metabolized to pharmacologically inactive products by the cytochrome P450 3A iso-enzymes. However, there have been few reports of the consequences of drug interactions between taxanes and other drugs metabolized by the cytochrome P450 pathway. To the best of our knowledge, this is the first case report of the potentially life-threatening interaction that can occur between docetaxel and the protease inhibitors lopinavir and ritonavir.Case presentationA 30-year-old Caucasian woman presented with symptoms suggestive of severe docetaxel toxicity, that is, prolonged myelosuppression, grade 4 mucositis and desquamating rash, following the commencement of post-exposure prophylaxis for a needlestick injury. She had previously received docetaxel chemotherapy with minimal side effects.ConclusionThis case report highlights a probable and novel drug interaction between docetaxel and lopinavir and/or ritonavir, which is largely unreported in the medical literature. Even though these interactions may be more relevant in the field of HIV medicine, knowledge of these interactions is also beneficial to oncologists and dermatologists, as well as those providing acute medical care.

Drs. Ghaznavi and Bhagwagar Reply

Back to table of contents Previous article Next article Letters to the EditorFull AccessDrs. Ghaznavi and Bhagwagar ReplySHARMIN GHAZNAVI M.D., Ph.D.ZUBIN BHAGWAGAR M.D., Ph.D., M.R.C.Psych.,SHARMIN GHAZNAVI M.D., Ph.D.Search for more papers by this authorZUBIN BHAGWAGAR M.D., Ph.D., M.R.C.Psych.Search for more papers by this author,Published Online:1 Dec 2008https://doi.org/10.1176/appi.ajp.2008.08071105rAboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: We thank Dr. Caetano for expressing interest in our article. To summarize, we reported on a patient who was treated with clozapine, 750 mg/day, and valproic acid, 1500 mg/day, for several years without incident. The first episode of clozapine-induced neutropenia occurred 1 month following the addition of donepezil to our patient’s treatment regimen. Dr. Caetano raises two related points regarding this initial episode of neutropenia. First, donepezil does not activate/inhibit enzymes that influence clozapine or valproic acid (1A2, 2D6, 3A4). Second, it is possible that valproic acid was responsible for increased clozapine concentration, leading to neutropenia. We agree that valproic acid can lead to increased concentrations of clozapine (1) , which we noted in our article. In fact, we raised the possibility that the combination of clozapine and valproic acid may confer a greater risk of later onset neutropenia in some patients. However, the fact that our patient was treated for years with the combination of clozapine and valproic acid without incident suggests that we cannot dismiss the setting in which our patient developed neutropenia, namely the addition of donepezil. To further address this point as well as the comment by Dr. Caetano pertaining to donepezil’s effect on the P450 isoenzymes 2D6 and 3A4, donepezil, to the best of our knowledge, is metabolized by the isoenzymes 2D6 and 3A4 (2) , which are also responsible for the metabolism of clozapine. Thus, it is possible that donepezil may have led to increased serum levels of clozapine and placed our patient at greater risk for developing neutropenia. At the time of the second clozapine rechallenge, our patient was being treated with risperidone, and clozapine was added to the regimen. Given that risperidone is known to increase serum levels of clozapine (3) , we concluded that the combination of clozapine and risperidone may have been responsible for neutropenia in our patient on that occasion. Thus, although we cite that risperidone alone carries a risk for neutropenia (4) , we do not feel that the drug was the primary offender and agree with Dr. Caetano that risperidone likely increased clozapine serum levels that led to neutropenia in our patient, and we appreciate the opportunity to clarify this point. Finally, Dr. Caetano suggests that lamotrigine should be avoided because it increases clozapine serum concentration. Indeed, there has been a case report of a threefold increase in serum concentration with the addition of lamotrigine (5) . However, Wong and Delva (6) , in their review of treatment for clozapine-induced seizures, recommended lamotrigine for its relative lack of effect on serum clozapine levels. We would therefore advise caution when prescribing lamotrigine as a secondary prophylaxis for clozapine-induced seizures rather than avoiding one of two (gabapentin) agents that are effective for clozapine-induced seizures and which demonstrate a relative lack of interactions with clozapine compared with valproic acid (6) . New Haven, Conn.The authors’ disclosures accompany the original article.This letter (doi: 10.1176/appi.ajp.2008.08071105r) was accepted for publication in August 2008.

Maraviroc: farmacocinética, interacciones y mecanismo de acción

Maraviroc (MVC, Celsentri) is an allosteric and reversible inhibitor of the CCR5 chemokine coreceptor. MVC is the first marketed CCR5 antagonist and the only oral entry inhibitor approved so far for the treatment of HIV infection. It has been approved for adults with previous antiretroviral exposure. MVC exclusively inhibits the replication of R5- tropic HIV-1 variants after binding to the transmembrane CCR5 receptor cavity. MVC is rapidly absorbed following oral administration, and plasma T(max) is achieved within 0.5- 4 hours after a 300 mg dose. Renal clearance is approximately 10-12 L/h. MVC is a substrate of the cytochrome P450 isoenzyme 3A4; therefore dose adjustments are required when co-administrated with other drugs that induce or inhibit CYP3A4. In addition, MVC dose adjustments are advised in patients with renal failure (CLcr <80 ml/min) only if they receive CYP3A4 inhibitors.

Bortezomib: A novel chemotherapeutic agent for hematologic malignancies

The pharmacology, pharmacokinetics, clinical efficacy, safety, dosage and administration, place in therapy, and cost of bortezomib in the treatment of multiple myeloma and mantle cell lymphoma are reviewed. Bortezomib is a modified dipeptidyl boronic acid that disrupts essential intracellular pathways by inhibiting proteasomes. The drug is metabolized by cytochrome P-450 isoenzymes 3A4, 2C19, and 1A2 to four inactive metabolites. Bortezomib was initially developed for the treatment of multiple myeloma based on the findings of early in vitro studies of patients with multiple myeloma who received at least one prior course of treatment; the drug received approval for the treatment of mantle cell lymphoma based on a single, noncomparative, Phase II study of previously treated patients. Significant toxicities have been reported with the use of bortezomib, including peripheral neuropathy, neutropenia, and thrombocytopenia. The dosage of bortezomib recommended by the manufacturer is 1.3 mg/m(2) per dose administered as an i.v. bolus injection twice weekly on days 1, 4, 8, and 11 of a three-week cycle. It is not necessary to adjust the dosage of bortezomib in patients with renal impairment. Bortezomib is being investigated as a treatment for several other malignant conditions. The current wholesale price of bortezomib is $1,322.40 for a single-use vial containing 3.5 mg of bortezomib lyophilized powder, with one course of treatment costing approximately $27,500 in drug cost alone. Bortezomib, an antineoplastic agent that reversibly inhibits the 26S proteasome, offers an important treatment option for patients with multiple myeloma or mantle cell lymphoma.

Effect of coadministration of ketoconazole, a strong CYP3A4 inhibitor, on pharmacokinetics and tolerability of motesanib diphosphate (AMG 706) in patients with advanced solid tumors

Motesanib diphosphate is a novel angiogenesis inhibitor selectively targeting vascular endothelial growth factor receptors 1, 2, and 3; platelet-derived growth factor receptor and stem cell factor receptor. The purpose of this phase 1b, drug-drug interaction study was to investigate the effect of ketoconazole, a strong inhibitor of the cytochrome P450 3A4 isoenzyme, on the pharmacokinetics and tolerability of motesanib diphosphate. Fourteen patients with advanced solid tumors refractory to standard treatment were enrolled and received motesanib diphosphate 50 mg once daily from day 1 through 15. Patients were randomized to receive a single oral dose of ketoconazole 400 mg either on day 8 (Sequence 1; n = 7) or day 15 (Sequence 2; n = 7), while pharmacokinetic samples were collected. After completion of this part (day 16), 13 patients received an escalated once-daily dose of motesanib diphosphate 125 mg. Evaluable pharmacokinetic data (n = 12) suggest that ketoconazole modestly increased motesanib exposure. The motesanib area under the concentration-time curve (AUC) from 0 to 24 h increased by 86% (90% CI, 1.50-2.29; P < 0.001) and the maximum plasma concentration (C (max)) by 35% (90% CI, 1.12-1.64; P = 0.02), compared with motesanib diphosphate administration alone. The tolerability profile (with or without ketoconazole coadministration) was consistent with that from other motesanib diphosphate monotherapy studies. Treatment-related adverse events were mild to moderate and commonly included fatigue (50% of patients), hypertension (43%), diarrhea (21%), dizziness (14%), paresthesia (14%), and vomiting (14%). Hypertension was the most common related grade 3 event (21%). No grade 4 or 5 treatment-related adverse events occurred.

Concurrent Administration of Sirolimus and Voriconazole: A Pilot Study Assessing Safety and Approaches to Appropriate Management

To assess the use and safety of concurrent administration of voriconazole and sirolimus-which is contraindicated-and to determine approaches for appropriately managing patients who receive both drugs. Retrospective medical record review. University-affiliated medical center. Thirty-one cases in 23 inpatients who received at least one dose of voriconazole and sirolimus concomitantly within a 24-hour period. Data on sirolimus and voriconazole indications, doses, routes, frequencies, and administration times; number of days of coadministration; and sirolimus dosage adjustments were collected. In addition, data on laboratory values, adverse events, sirolimus concentrations, and concomitant drugs, including cytochrome P450 (CYP) 3A isoenzyme and P-glycoprotein inhibitors and inducers, were collected for 7 days before, during, and for 14 days after coadministration. No cases of elevated sirolimus concentrations (>20 mg/ml) occurred in patients stabilized with voriconazole before starting low-dose sirolimus 0.5-1 mg/day, or in those stabilized with sirolimus 0.5-2 mg/day who had baseline sirolimus concentrations of 12 ng/ml or lower and whose sirolimus dose was decreased by 50% before the addition of voriconazole. In contrast, elevated sirolimus concentrations were experienced in patients receiving sirolimus doses of 4 mg/day or higher who had sirolimus concentrations of 12 ng/ml or higher and whose sirolimus dose was not decreased before addition of voriconazole. In a patient who received sirolimus with itraconazole, a strong CYP3A isoenzyme inhibitor, one case of only a minimal increase in the sirolimus concentration occurred after the addition of voriconazole. Sirolimus and voriconazole can be safely coadministered as long as consideration is given to which agent the patient receives first, the sirolimus dosage, sirolimus concentrations, and concurrent disease states and CYP3A isoenzyme inhibitors. Sirolimus concentrations should be closely and routinely monitored before, during, and after coadministration of voriconazole and other CYP3A isoenzyme inhibitors. Based on the results of this pilot study, a protocol on the management of this drug combination will be implemented and prospectively evaluated for efficacy and safety.

Cinacalcet in HIV haemodialysis patients.

Sir, Cinacalcet HCL (MIMPARA®), a positive allosteric modulator of the calcium-sensing receptor (CaR) on the surface of the parathyroid glands, reduces serum parathyroid hormone (PTH) levels in more than 80% of haemodialysis (HD) patients [1]. The efficacy and safety of cinacalcet has been demonstrated in several studies [1,2], but its use in HIV patients on chronic dialysis is not described. We report two HD patients with HIV infection treated simultaneously with anti-retroviral therapy and cinacalcet. A 24-year-old black woman was admitted in July 2002 for end-stage renal disease (ESRD) of unknown origin that required chronic HD. Simultaneously, HIV-1 infection was diagnosed. A tritherapy with efavirenz 600 mg, lamivudine 25 mg and didanosine 100 mg per day was initiated in January 2004, resulting in sustained undetectable HIV plasma viral load and stable T4 levels (>550/mm3). Cinacalcet was started in May 2007 at 30 mg/day and progressively increased to 90 mg without any efficacy (intact parathyroid hormone (iPTH) > 1000 pg/ml). In December 2007, cinacalcet was stopped and a parathyroidectomy was performed. Histological examination revealed a bilateral parathyroid adenoma. Efavirenz residual serum concentration after surgery and cinacalcet withdrawal was 1.5 μg/ml (normal range: 1.1–4 μg/ml). A 45-year-old Caucasian man was treated by chronic HD for ESRD of unknown aetiology since July 2003. HIV-1 and hepatitis B virus (HBV) co-infection was discovered at the time of dialysis initiation. A combination of efavirenz 600 mg, lamivudine 50 mg, didanosine 125 mg per day and tenofovir 245 mg per week resulted in undetectable HBV and HIV plasma viral load with sustained stable T4 levels (>600/mm3). Because of high serum iPTH (>1000 pg/ml), cinacalcet was initiated in May 2007 at 30 mg per day and further increased to 120 mg in November 2007 without efficacy. Efavirenz mean residual serum concentration on three consecutive measurements under cinacalcet therapy (120 mg) was 1.3 ± 0.5 (SD) μg/ml. The two patients received concomitant treatment with sevelamer, calcium carbonate and vitamin D3 during cinacalcet therapy. In both the cases, tolerance of cinacalcet and anti-retroviral treatment was good. Monthly monitoring of pancreatic and liver enzymes and serum calcium levels was not modified. Analysis of the literature shows that more than 80% of HD patients on cinacalcet therapy achieve an ≥30% reduction in iPTH level from the baseline over 6 months [1]. In our cases, whereas cinacalcet was administered for more than 6 months, no effect on iPTH was observed despite increased cinacalcet dosage. Little is known about the pathophysiology of resistance to cinacalcet. A role for non-compliance to the drug was excluded in both the cases. Defective sensitivity of the parathyroid cell to the calcimimetic drug has been proposed. Additionally, a relative resistance to cinacalcet was demonstrated in the case of severe decreased expression of CaR in parathyroid glands [3]. In our cases, resistance to cinacalcet was likely the result of drug interaction. Cinacalcet is metabolized through cytochrome P450 (CYP) isoenzymes 3A4, 2D6 and 1A2. In vitro studies have demonstrated that cinacalcet is a potent inhibitor of CYP2D6. Additionally, data suggest that during concomitant treatment with cinacalcet, dose adjustment may be necessary for CYP3A4 and CYP1A2 inductors or inhibitors [4]. As the metabolism of lamivudine, didanosine and tenofovir do not involve CYP450, the culprit drug seems to be efavirenz. Efavirenz is metabolized via CYP450, particularly by 3A4 and 2B6 isoenzymes. Although efavirenz is an in vitro inhibitor for 2C9, 2C19, 3A4, 2D6 and 1A2 isoenzymes, it has been demonstrated in humans that efavirenz can be inductor for CYP450 enzymes and can also induce its own metabolism by this mechanism [5,6]. This enzymatic induction, especially for CYP3A4 isoenzyme, is probably responsible for most drug interactions with efavirenz. Despite the absence of a known pharmakokinetics interaction between cinacalcet and efavirenz, enzymatic induction of CYP3A4 metabolism by efavirenz is probably responsible for therapeutic failure of cinacalcet in the present cases. Unfortunately, this hypothesis could not be verified, as the measurement of the serum cinacalcet level is not currently available. However, a role for decreased numbers of CaR or defective sensitivity of parathyroid cells cannot be excluded. In summary, cinacalcet in HD patients with chronic HIV infection treated by efavirenz seems inappropriate. Nephrologists need to be aware of this rare potential interaction. Surgical parathyroidectomy should be recommended. Conflict of interest statement. None declared. The results presented in this paper have not been published previously in whole or part, except in abstract format.

PMH15 ANALYSIS OF POTENTIAL DRUG-DRUG INTERACTION PAIRS ASSOCIATED WITH ANTIPSYCHOTICS AMONG MEDICAID PATIENTS WITH SCHIZOPHRENIA OR BIPOLAR DISORDER

Objectives: Patients with schizophrenia, schizoaffective disorder, or bipolar disorder often receive multiple medications as part of their treatment regimens. Since many antipsychotics are metabolized by cytochrome P450 (CYP450) isoenzymes (1A2, 2D6, and 3A4), we proposed to assess the risk of receiving potential drug-drug interaction (DDI) pairs associated with the inhibition or induction of CYP450 isoenzymes.

Effect of ketoconazole on the pharmacokinetics of maribavir in healthy adults.

Maribavir, an oral antiviral drug with activity against cytomegalovirus, is currently undergoing studies to assess its efficacy and safety as cytomegalovirus prophylaxis following stem cell or solid organ transplantation. The main objective of this study was to assess the effects of oral ketoconazole, a potent inhibitor of the cytochrome P450 3A4 (CYP3A4) isoenzyme, on the pharmacokinetics of maribavir. This was an open-label crossover study with 20 healthy adults. Subjects were administered a single dose of maribavir at 400 mg. After a washout period, subjects received a single dose of ketoconazole at 400 mg followed by a single dose of maribavir. Blood samples were collected for each drug sequence, and pharmacokinetic parameters for maribavir and its principal metabolite, VP 44469, were determined. Safety was evaluated by physical examination, clinical laboratory testing, 12-lead electrocardiogram, and monitoring for adverse events. Ketoconazole moderately reduced the clearance of both maribavir and VP 44469; oral clearance values were 35% and 13% lower, respectively, for maribavir-plus-ketoconazole treatment than for maribavir alone. Based on the assumption of complete inhibition of CYP3A4 activity, CYP3A4 is responsible for 35% of the overall clearance of maribavir. Treatment was generally well tolerated. The most-common adverse event was dysgeusia (taste disturbance), reported by nine (47%) and seven (35%) subjects in the maribavir alone and maribavir-plus-ketoconazole groups, respectively. The pharmacokinetic findings, in combination with the acceptable tolerability within the maribavir and maribavir-plus-ketoconazole treatment groups, suggest that no dose adjustment of maribavir is necessary when coadministered with CYP3A4 inhibitors or substrates.