Need For Dose Adjustment Research Articles

GRP-058 Establishment of a Programme to Detect Drug Interactions Complementary to Electronic Prescriptions

BackgroundOurs is a 110-bed regional hospital with electronic prescribing throughout. The electronic prescription programme offers allergy alert systems and the need for dosage adjustment in renal and hepatic impairment. However,...

Pharmacokinetics (PK) of panitumumab in a single patient with metastatic colorectal cancer (mCRC) and liver dysfunction.

594 Background: Panitumumab is used for the treatment of metastatic KRAS wild type (WT) colorectal cancer (mCRC). It is likely that many of these patients will present with liver metastases and some with liver dysfunction. The pharmacokinetics in patients with hepatic impairment are unknown and dosage adjustments are undetermined. Here, we present a case of a patient with progressive mCRC and liver dysfunction. Methods: A heavily pre-treated KRAS WT mCRC patient with liver disease Child-Pugh class B was treated with two-weekly 6 mg/kg panitumumab. The patient received 2 doses of 490 mg iv panitumumab after which progressive disease was documented. Toxicities were graded using CTCAEv4.0. Serum samples were collected and panitumumab concentrations were determined using a validated immunoassay. PK parameters after the first dose, including dose-normalized AUC from time zero–day 14, clearance (CL), and elimination half-life (T1/2), were estimated via trapezoidal non compartmental methods. Data was compared to historical data from a normal population as reported by Stephenson (Clin Colorectal Cancer 2009). Values within the range of the mean ± 1 standard deviation (SD) were considered not deviant. Results: Calculated AUC after the first dose of 6 mg/kg panitumumab in this patient with hepatic dysfunction was 877 μg*day/mL (Stephenson’s cohort 1: 744 ± 195 μg*day/mL). Estimated T1/2was 3.58 days (5.28 ± 1.90 days) and CL was 6.9 mL/day/kg (8.21 ± 3.79 mL/day/kg). Estimated PK parameters during the first cycle were inside reported mean ± 1 SD of historical controls without liver dysfunction. No toxicity was reported during treatment, particularly, no diarrhea and skin toxicity. Conclusions: The pharmacokinetics of panitumumab in this patient suffering from colorectal cancer with liver dysfunction Child-Pugh class B was similar when compared to patients with adequate liver functions. Moreover, no substantial toxicity was detected. The here presented data may help clinical decision making in real life practice. Two-weekly panitumumab monotherapy seems to be safely applicable in patients with KRAS WT mCRC and hepatic dysfunction without the need for dose adjustments.

Clinical overview of linagliptin, a dipeptidyl peptidase-4 inhibitor, in patients with Type 2 diabetes mellitus

Linagliptin is a pharmacologically unique, orally active, once-daily dipeptidyl peptidase-4 inhibitor indicated for the treatment of hyperglycemia in patients with Type 2 diabetes mellitus. Compared with other dipeptidyl peptidase-4 inhibitors, linagliptin has a favorable pharmacokinetic profile with a primarily nonrenal route of elimination that avoids the need for dose adjustment in patients with renal impairment. When administered as monotherapy or in combination with other antihyperglycemic drugs, linagliptin treatment leads to clinically meaningful reductions in glycated hemoglobin, fasting plasma glucose and postprandial plasma glucose levels. In addition, pancreatic β-cell function is enhanced. Linagliptin treatment is well tolerated, with weight-neutral effects and no increased risk of hypoglycemia. Of note, linagliptin treatment was associated with a significantly reduced risk of cardiovascular events in clinical trials of ≤2 years, although this finding remains to be confirmed in larger and longer clinical outcomes studies.

Novel Methods for Assessing Oral Direct Factor Xa and Thrombin Inhibitors: Use of Point-of-Care Testing and Urine Samples

Rivaroxaban and dabigatran are new oral anticoagulants (NOACs) that inhibit directly factor Xa and thrombin, respectively. These NOACs effectively prevent thromboembolic complications using fixed doses without the need for dose adjustment according to laboratory results. About 60% of rivaroxaban is cleared from circulation by glomerular filtration, 30% of which is excreted as active drug. About 80% of dabigatran is excreted into urine as active compound. Accordingly, both NOACs can be determined in urine by means of chromatographic methods. Only a few laboratories are able to perform such methods, and results are not available within short time frames. New methods have to be developed to obtain results within minutes and possibly as point-of-care (POC) techniques. This testing may be useful for special patient populations such as those with acute deterioration of renal function due to any disease, before surgical interventions, during unexpected bleeding or thrombotic episodes while on therapy with NOACs, the oldest and youngest populations, pregnancy, suspicion of overdose and intoxication, and to determine adherence to therapy. Here we describe results of a POC qualitative assay using urine samples from patients on treatment with dabigatran and rivaroxaban.

Abstract P1-14-14: Neoadjuvant Sunitinib (S) Administered with Weekly Paclitaxel (P)/Carboplatin(C) in Patients (Pts) with Locally Advanced Triple-Negative Breast Cancer (TNBC): Preliminary Results from a Phase I/II Trial of the Sarah Cannon Research Institute.

Abstract Background: S is an oral, small molecule, multi-targeted tyrosine kinase inhibitor of vascular endothelial growth factor receptor, platelet-derived growth factor receptor, stem cell factor receptor, and colony-stimulating factor-1 receptor with demonstrated single agent activity in multiple tumor types including breast cancer. S's anti-proliferative and anti-angiogenic activity stimulated interest in combining it with a variety of chemotherapy regimens. In the previously reported Phase I portion of this trial, S 25mg PO daily was determined feasible in combination with weekly P and C, an active regimen for TNBC. We now report the feasibility and efficacy of the phase II evaluation of this combination as neoadjuvant therapy with pathologic complete response (pCR) as the primary endpoint. Methods: Eligibility criteria included: invasive adenocarcinoma, triple negative histology defined as ER/ PR negative (<10% IHC staining) as well as HER2-negative (IHC 0–1+ or FISH neg), clinical T1-3, N0-1, M0 with clinical N3, T4 and T1 N0 M0 tumors excluded, ECOG PS 0–2, normal LVEF, and adequate organ function. All pts received P 70mg/m2 (Days 1, 8, 15) + C AUC=5 (Day 1) with S 25mg PO daily q 28 days for 6 cycles. Response assessments were performed after 3 cycles, and in the absence of disease progression or unacceptable toxicity, study treatment continued for 3 additional cycles. Postoperatively, pts resumed S 25 mg qd until 52 weeks from D1. Definition of pCR was an absence of invasive cancer in both breast and lymph nodes. A pCR rate of ≥ 30% would warrant additional evaluation of this regimen. Results: The phase II portion of this trial enrolled 36 pts from 2/2011 to present. This analysis is based on 22 pts evaluable for toxicity and efficacy. Median tumor size was 4 cm with 68% designated T2 and 27% as T3 and 63% with clinical N1 or N2 disease. A median of 3 preoperative cycles was delivered. Best clinical response was; cCR − 1 (5%), cPR − 9 (41%), cSD − 6 (27%), PD − 1 (5%), UE − 5 (22%). Pathologic responses are as follows: ypCR −2 pts (9%), PR2 (residual invasive cancer in breast, negative lymph nodes −1 pt, PR3 (residual invasive cancer in breast and lymph nodes) −1 pt. 3 pts of the 4 with surgical outcomes completed all 6 cycles of treatment; 2 of which had pCR. Poor tolerance/toxicity resulted in 8 pts proceeding to surgery early/or discontinuation and 2 pts experienced progression; data is pending in 8 pts. Grade 3/4 hematologic toxicity consisted of neutropenia-15 pts (68%) with fever in 2 (9%), anemia −9 pts (41%), and thrombocytopenia-8 pts (36%). No G3/4 non-hematologic toxicity was present in >5% of pts. Conclusions: The addition of sunitinib to paclitaxel and carboplatin was accompanied by significant hematologic toxicity resulting in the inability to deliver the planned study therapy. Treatment discontinuations were frequent as was the need for dose adjustments and modifications. The sunitinib-paclitaxel/carboplatin combination evaluated in this study is not recommended for further use in locally advanced breast cancer. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-14-14.

Reduction in Initial Length of Stay with Rivaroxaban Single-Drug Regimen versus LMWH-VKA Standard of Care: Findings from the EINSTEIN Trial Program

AbstractAbstract 3419 BackgroundThe current standard of care for the treatment of symptomatic deep vein thrombosis (DVT) and pulmonary embolism (PE) is parenteral low molecular weight heparin (LMWH) or fondaparinux, overlapping with and followed by a vitamin K antagonist (VKA). According to guidelines, parenteral treatment should be discontinued only when patients have reached a stable level of anticoagulation with a VKA; defined as 2 consecutive measurements of international normalized ratio (INR) >2.0 at least 24 hours apart.Compared with the previous standard of care, continuous infusion of unfractionated heparin, LMWH has made outpatient treatment feasible and lowered the treatment burden for patients, while reducing healthcare system costs. However, based on local practice or initial severity of disease many patients, especially those with PE, are still hospitalized, with discharge delayed until parenteral treatment can be discontinued.Rivaroxaban is an oral anticoagulant that produces stable levels of anticoagulation without the need for dose adjustments or routine coagulation monitoring for acute or long-term treatment. With its oral mode of administration and without the need for parenteral bridging therapy, rivaroxaban has the potential to allow discharge based on a patient's clinical condition without the additional requirement of achieving adequate oral anticoagulation levels, thereby further reducing healthcare costs and increasing convenience for patients. AimsWe investigated the potential of rivaroxaban to reduce the length of initial hospitalization and the proportion of patients hospitalized, using data from the EINSTEIN DVT and EINSTEIN PE studies. MethodsThe EINSTEIN DVT and EINSTEIN PE studies were large, open-label, randomized, non-inferiority phase III trials comparing oral rivaroxaban (15 mg twice daily for 3 weeks, followed by 20 mg once daily) with dose-adjusted subcutaneous enoxaparin (1.0 mg/kg twice daily) overlapping with, and followed by, warfarin or acenocoumarol (INR 2.0–3.0). There were no instructions in the protocols of the studies with regard to hospital admission and/or discharge, which were left to the judgment of the attending physician.Length of hospital stay was evaluated from investigator records of dates of admission and discharge. All analyses were carried out in the intention-to-treat population using the van Elteren test, a stratified non-parametric test of significance, stratified by intended treatment duration. Analyses were exploratory with no adjustments for multiplicity. ResultsIn the EINSTEIN DVT trial, 1781 of 3449 (52%) patients were hospitalized for the qualifying event, with similar proportions in each treatment arm (Table). However, the median length of hospital stay was significantly shorter in the rivaroxaban arm compared with the enoxaparin/VKA arm (5.0 vs 8.0 days; p<0.0001). In the EINSTEIN PE trial, 4328 of 4832 (90%) patients were hospitalized, with similar proportions in each treatment arm. Again, the median length of hospital stay was significantly shorter in patients receiving rivaroxaban than in patients receiving enoxaparin/VKA (6.0 vs 7.0 days; p<0.0001). ConclusionThese results indicate that a single-drug anticoagulation regimen using rivaroxaban significantly reduces the length of hospital stay for patients admitted for DVT and/or PE, relative to standard of care. This has the potential to reduce the treatment burden for patients and healthcare systems.TableProportion of patients hospitalized and initial length of hospital stay in the EINSTEIN DVT and EINSTEIN PE studiesEINSTEIN DVTEINSTEIN PEPatient populationRivaroxaban (n=1731)Enoxaparin/VKA (n=1718)p-valueRivaroxaban (n=2419)Enoxaparin/VKA (n=2413)p-valueWith complete data on whether hospitalized, n1723171124122409Hospitalized, n (%)872 (50.6)909 (53.1)p=0.144*2163 (89.7)2165 (89.9)p=0.828*Not hospitalized, n (%)851 (49.4)802 (46.9)_249 (10.3)244 (10.1)_Hospitalized with complete data on length of stay, n871908_21602159_Median length of stay, days (interquartile range)5.0 (3.0–9.0)8.0 (4.5–10.0)p<0.0001†6.0 (4.0–9.0)7.0 (5.0–10.0)p<0.0001†*p-value obtained from Cochran–Mantel–Haenszel test stratified by intended treatment duration;†p-value obtained from a stratified Wilcoxon rank-sum test (van Elteren test) stratified by intended treatment duration. Disclosures:van Bellen:Bayer Brazil: Membership on an entity's Board of Directors or advisory committees. Prins:Bayer Healthcare: Consultancy, Honoraria. Bamber:Bayer Healthcare: Employment. Wang:Bayer Healthcare: Employment. Lensing:Bayer Healthcare: Employment.

Oral antidiabetic drugs in chronic renal diseases

Decline in renal function may increase plasma concentration of several drugs - including oral antidiabetics - with a possible need for dose adjustment in this patient population. In this review, the pathophysiology and progression of diabetic kidney diseases is summarized. Guidance is given about appropriate administration of oral antidiabetic drugs in chronic kidney diseases, based on approved product label information. In addition to pioglitazon, recent availability of the new dipeptidyl peptidase-4 inhibitor linagliptin provides another option for diabetic patients with renal impairment without the need for dose reduction due to its predominant enterohepatic elimination.

Significant Association Between GSTA1 Genotype and Busulfan Pharmacokinetics in Patients Conditioned for Hematopoietic Stem Cell Transplantation

Introduction: Busulfan (BU) is frequently used in high-dose conditioning regimens before hematopoietic stem cell transplantation (HSCT). Due to a narrow therapeutic range and large pharmacokinetic variability, BU dosing is usually guided by therapeutic drug monitoring. Glutathione S-transferases (GST) play an important role in the metabolism of BU, and GST gene variants may explain some of the interindividual variability in pharmacokinetics. The objective of the present study was to evaluate the association between GSTA1, GSTM1, and GSTT1 genotypes and BU pharmacokinetics. Methods: From February 2008 to January 2012, 114 adult patients (age 16-65 yrs) who received oral BU pre-HSCT were enrolled in this study. BU was given every 6 hrs from day -7 to -4 starting with fixed doses (˜1 mg/kg) the first day, followed by dose adjustments to approach a therapeutic target steady-state concentration (Css) of 900 ng/mL. Blood samples were drawn at 0, 30, 60, 90, 120, 180, 240 and 300 min after the 1st, 5th and 9th doses (day 1, 2 and 3, respectively) and BU plasma concentrations were measured by liquid chromatograpy with UV detection. GSTA1 haplotype was determined by melt curve genotyping analyzing the c.-69C>T (rs3957357) variant. Gene copy numbers of GSTM1 and GSTT1 were determined by quantitative real-time PCR using albumin as an internal reference gene. The genotyping assays were run on the LightCycler® 480 instrument. Results: Genotype frequencies were 39.5%, 35.1% and 25.4% for GSTA1C/C (*A/*A), C/T (*A/*B) and T/T (*B/*B), respectively. The proportion of patients carrying 0, 1 and 2 GSTM1 and GSTT1 gene copies were 43.9%, 45.6% and 10.5% and 15.8%, 44.7% and 39.5%, respectively. BU exposure (Css) was significantly different between GSTA1 genotype groups (P≤0.01). No significant associations were observed between GSTM1 and GSTT1 copy numbers, age or gender and BU pharmacokinetics. Stratified according to GSTA1 genotype, *B/*B and *A/*B carrieres demonstrated median 14% and 9% higher (P≤0.01) dose adjusted BU Css on day 1, and 22% and 15% higher (P≤0.04) Css on day 2, compared to *A/*A patients. Clearance/bioavailability (Cl/F) was median 13% and 9% lower (P≤0.02) on day 1 and 22% and 15% (P≤0.04) lower on day 2 among *B/*B and *A/*B vs. *A/*A carrieres, respectively. Furthermore, the *B/*B and *A/*B groups demonstrated BU exposure significantly above the therapeutic target Css of 900 ng/mL on day 1 and 2 (P≤0.001). The initial BU dose was median 1.0 (0.8-1.1) mg/kg in all GSTA1 groups. Following two days of dose adjustments, BU doses the third day of therapy were 14% and 8% lower (P≤0.03) among *B/*B and *A/*B patients compared to *A/*A patients. No significant differences were observed in BU Css or Cl/F between GSTA1 groups on day 3. Conclusion: The data demonstrate an association between GSTA1 genotype and BU Css and Cl/F the first two days of BU conditioning therapy. Genotyping GSTA1 prior to HSCT may allow better prediction of oral BU kinetics, reduce the need for dose adjustments and thereby improve clinical outcomes following high-dose BU conditioning.

Unrecognized renal insufficiency and chemotherapy-associated adverse effects among breast cancer patients

Several studies have shown that more than half of cancer patients have unrecognized renal insufficiency (RI), which is a reduced glomerular filtration rate (GFR) with normal serum creatinine. The aim of this study was to determine whether unrecognized RI is associated with an increased risk for chemotherapy-associated adverse effects in breast cancer patients treated with combined doxorubicin and cyclophosphamide treatment. GFR was estimated for 95 breast cancer patients from January 2005 to August 2009 using the Cockcroft-Gault formula. Unrecognized RI was defined as GFR less than 75 ml/min/1.73 m and the patients were grouped according to their estimated GFR. Logistic regression models were used to assess the effect of GFR on clinical outcomes. In total, 49 (52%) patients experienced at least one of the following chemotherapy-associated adverse effects during the course of treatment: an episode of neutropenic fever with hospital admission, a delay in chemotherapy treatment for a medical reason, a need for dose adjustment because of toxicity of the chemotherapeutic drugs, and the need for use of granulocyte colony-stimulating factor. The incidence of these adverse effects occurred more frequently in patients with GFR less than 75 compared with patients with GFR at least 75 (64 vs. 42%, odds ratio 5.29, 95% confidence interval 2.10-13.33) and remained statistically significant after adjustment for age, BMI, and initial doses of chemotherapeutic drugs (odds ratio 3.56, 95% confidence interval 1.08-11.67). Neutropenic fever, dose delay, and dose adjustment as separate outcomes occurred more frequently in the GFR less than 75 group but lost statistical significance after adjustment. Our results demonstrate that unrecognized RI is associated with an increased risk for chemotherapy-associated adverse events in this patient population. Further prospective studies are required to determine whether a dose reduction in patients with unrecognized RI reduces adverse effects without adversely affecting the benefit of treatment.

Pharmacokinetic and tolerability profile of pridopidine in healthy-volunteer poor and extensive CYP2D6 metabolizers, following single and multiple dosing

Pridopidine is being developed for the treatment of impaired motor function associated with Huntington's disease and belongs to a new class of compounds known as dopidines, which act as dopaminergic stabilizers. In vitro studies have shown that pridopidine is a substrate for the P450 cytochrome 2D6 enzyme (CYP2D6), and clinical data show that the half-life of pridopidine is different following single dosing versus at steady state. To further investigate the pharmacokinetic profile of pridopidine and to establish whether dose adjustment is needed in poor CYP2D6 metabolizers, a single-centre, open-label, multiple-dose study in healthy volunteers was performed. In total, 24 extensive CYP2D6 metabolizers (EMs) and 12 poor CYP2D6 metabolizers (PMs) were enrolled. Both groups received 45mg pridopidine twice daily (b.i.d.). Plasma samples were taken during the first day of b.i.d. dosing (Day 1) and at steady state, following 14days of b.i.d. dosing. At Day 1, total exposure in PMs was almost three times higher than those in EMs (AUC0-∞=11,192 and 3,782h·ng/mL, respectively; PM/EM ratio=2.96; p<0.001). However, at steady state, PMs and EMs had comparable exposure due to a reduction in pridopidine elimination in EMs over time. Thus, at steady-state peak (C max) and total (AUC0-24) exposures were only 1.24 and 1.29 times higher, respectively, in PMs than EMs. These results support that pridopidine is a CYP2D6 auto-inhibitor. Pridopidine was well tolerated in both EMs and PMs. The slightly higher exposure level in PMs at steady state does not indicate a need for dose adjustment or genotyping for CYP2D6 metabolizer status.

Treatment of Diabetes Prior to and after Bariatric Surgery

The number of patients undergoing bariatric surgery for morbid obesity is increasing. Type 2 diabetes is common among patients undergoing bariatric surgery. The effect of bariatric surgery on glycemia is profound in patients with diabetes and might vary between different bariatric surgical procedures. Therefore, almost invariably, there is a need to adjust antidiabetic drug dosages in the postoperative period in order to prevent hypoglycemia. Moreover, preoperatively, very low calorie diet protocols are applied in many centers to facilitate surgery by reducing liver volume. Because low caloric intake will increase insulin sensitivity, there is also a need for dose adjustments of glucose-lowering drugs during this period as well. Guidelines for adjustments of antidiabetic treatment before and after bariatric surgery are scarce. In this article, an overview of different bariatric surgical procedures as well as their effects on diabetes are presented. Recommendations on the perioperative antidiabetic treatment are proposed.

Anidulafungin—A New Therapeutic Option for Candida Infections in Liver Transplantation

IntroductionIn the last years, the incidence of Candida infections in liver transplant recipients has increased with still higher morbidity and mortality. Anidulafungin, a new echinocandin that does not interfere with cytochrome p450, shows no need for dosage adjustment based upon renal or hepatic function or weight. AimTo analyze tolerance to and microbiologic and clinical efficacy of Anidulafungin to treat Candida infections in liver transplant patients. Materials and MethodsThis phase 3b, prospective, open-label, single-center study focused on liver transplant patients with a suspected and/or diagnosed Candida infection. The patients received Anidulafungin intravenously, optionally followed by oral therapy with azoles. The primary endpoint was the global response at the end of therapy; secondary endpoints were the efficacy of intravenous therapy, 90-day survival, as well as tolerance for and interaction with immunosuppresants. ResultsWe considered 42 consecutive liver recipients transplanted between 2009 and 2010 among whom 13 (31%) were recruited for the study and four patients were treated with Anidulafungin as empirical therapy, six as preemptive therapy, and three as targeted treatment for documented candidemia (7.1%). The immunosuppressive regimen consisted of tacrolimus and low dose of steroids. The Candida species were: C albicans (50%), C glabrata (12.5%), C parapsilosis (12.5%), C krusei (12.5%), C lusitaniae (6.2%), C tropicalis (6.2%), and multiple others (25%). The principle site of isolation was the bile (53.8%), followed by the bloodstream (23.1%), central venous catheters (15.4%), bronchoalveolar lavage (15.4%), peritoneum (7.7%), and other locations (7.7%). Two patients (15.4%) died of severe sepsis with multiple organ failure. There was no alteration of hepatic enzymes, indices of cholestasis or changes in immunosuppressant drug levels. ConclusionAnidulafungin was an effective, safe, and well-tolerated drug. There were neither toxic effects to the grafts or adverse interactions with immunosuppresants.

An update on the use of ambrisentan in pulmonary arterial hypertension

The development of effective oral treatments that are capable of modulating the activity of endothelin receptor 1 (ET-1) represents a significant milestone in the field of pulmonary arterial hypertension (PAH). Randomized clinical trials confirm that endothelin receptor antagonist (ERA) treatments confer significant improvements on important clinical endpoints, such as exercise capacity, functional class, quality of life and pulmonary hemodynamics. Moreover, ERAs may prevent or delay clinical worsening and retard disease progression. Ambrisentan is a propanoic acid-based ERA, showing preferential affinity for the type A ET-1 over the type B receptor. It provides another valuable, effective treatment option in PAH. Two large, randomized-placebo controlled trials demonstrated the efficacy of ambrisentan in PAH at improving exercise tolerance as measured by the 6 min walk distance. Additional secondary measures of improvement including time to clinical worsening, survival, functional class, quality of life and hemodynamic variables have been reported in clinical trials. A favorably low incidence of aminotransferase elevation indicating lower hepatic toxicity than other ERAs has been observed. Ambrisentan can be safely administered with warfarin or sildenafil without the need for dose adjustment of either therapy. A once daily oral medication with relatively few side effects is an attractive option, especially as the use of therapies in combination continues to increase. Long-term data and hemodynamic data confirm the benefits can be compared with other ERAs with fewer drug-drug interactions and a better liver safety profile.

Population Pharmacokinetics of Fingolimod Phosphate in Healthy Participants

Fingolimod (FTY720) is a sphingosine 1-phosphate receptor (S1PR) modulator currently being evaluated for the treatment of multiple sclerosis. Fingolimod undergoes phosphorylation in vivo to yield fingolimod phosphate (fingolimod-P), which modulates S1PRs expressed on lymphocytes and cells in the central nervous system. The authors developed a population model, using pooled data from 7 phase 1 studies, to enable characterization of fingolimod-P pharmacokinetics following oral administration of fingolimod and to evaluate the impact of key demographic variables on exposure. The fingolimod-P concentration-time course after either single or multiple doses of fingolimod was described by a 2-compartment model with first-order apparent formation and elimination, lag time in the apparent formation, and dose-dependent relative bioavailability and apparent central volume of distribution. Body weight and ethnicity were identified as demographic covariates correlated with the disposition of fingolimod-P. Model predictions indicated no need for dose adjustment of fingolimod based on body weight; the effect of ethnicity on the disposition of fingolimod requires further investigation. The accurate prediction of the pharmacokinetic profile of fingolimod-P determined empirically in 2 large phase 3 trials provides external validation of the model.

Lack of effect of tofacitinib (CP‐690,550) on the pharmacokinetics of the CYP3A4 substrate midazolam in healthy volunteers: confirmation of in vitro data

• Tofacitinib (CP-690,550) is a novel, oral Janus kinase inhibitor being investigated as a targeted immunomodulator and disease-modifying therapy in rheumatoid arthritis. • Non-renal elimination accounts for 70% of the total clearance of tofacitinib and the metabolism is primarily mediated by cytochrome P450 (CYP) 3A4. • This study was required to determine the effect of tofacitinib on the in vivo pharmacokinetics of a sensitive CYP3A4 substrate. • The pharmacokinetics of midazolam, a sensitive CYP3A4 substrate, are not altered when co-administered with tofacitinib in healthy subjects. • Tofacitinib is unlikely to affect the clearance of drugs metabolized by CYP enzymes. • There is no need for dose adjustments of CYP substrates when co-administered with tofacitinib. To investigate inhibitive and inductive effects of tofacitinib (CP-690,550), a Janus kinase inhibitor, on CYP3A4 function via in vitro and in vivo studies. In vitro experiments were conducted to assess the inhibition and induction potential of tofacitinib for major drug metabolizing enzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4). A phase 1, randomized, open-label, two-way crossover study (NCT00902460) was conducted to confirm the lack of inhibitive/inductive effect on a sensitive CYP3A4 substrate, midazolam, in healthy subjects. Midazolam pharmacokinetics were assessed over 24 h following single dose 2 mg administration prior to administering tofacitinib and after twice daily dosing of tofacitinib 30 mg for 6 days. The primary endpoint was midazolam area under the concentration-time profile, from time 0 to infinity (AUC(0,∞)). In vitro studies demonstrated low potential for CYP inhibition (IC(50) estimates tofacitinib > 30 µm), CYP3A4 mRNA induction (observed at tofacitinib concentrations ≥ 25 µm) and no effect on enzymatic activity of CYP substrates. In the human study, AUC(0,∞) adjusted geometric mean ratio for midazolam plus tofacitinib to midazolam alone was 103.97% [90% confidence interval (CI) 95.57, 113.12], wholly within the pre-specified acceptance region (80, 125). The 90% CI for the ratio of adjusted geometric means of maximum plasma concentration (C(max) ) (95.98, 108.87) was also wholly within this acceptance region. These data confirm a lack of an inhibitive or inductive effect of tofacitinib on CYP3A activity in humans and, in conjunction with in vitro data, support the conclusion that tofacitinib is unlikely to influence the CYP enzyme system as a whole.

Incretin Therapies in the Management of Patients with Type 2 Diabetes Mellitus and Renal Impairment

Renal impairment (RI) is common among patients with type 2 diabetes mellitus (T2DM), and these patients also experience an age-related decline in renal function. At the same time, treatment options are more limited and treatment is more complex, particularly in patients with moderate or severe RI due to contraindications, need for dose adjustment and/or regular monitoring, and side effects, such as fluid retention and hypoglycemia, which are a more serious concern in this patient population. Incretin therapies, consisting of the injectable glucagon-like peptide-1 (GLP-1) receptor agonists and the oral dipeptidyl peptidase-4 (DPP-4) inhibitors, are a promising new class of antihyperglycemic drugs. In the overall population, they improve glycemic control in a glucose-dependent manner and are not likely to cause hypoglycemia, representing a clear advantage in at-risk populations. Data regarding use of these agents in renally impaired patients have started to emerge, and the objective of this article is to provide an overview of the currently available data and the potential role of these novel agents in the management of patients with T2DM and RI. Data for the GLP-1 receptor agonists in patients with moderate or severe RI are still limited, with no trials dedicated to these populations currently published. In addition, their potential to cause gastrointestinal side effects may limit use in patients with RI due to the risk of dehydration and hypovolemia. The use of GLP-1 receptor agonists in patients with moderate or severe RI is therefore, at present, underlying caution and/or restrictions. On the other hand, data from specific trials in patients with moderate or severe RI are now becoming available for most of the DPP-4 inhibitors. These studies demonstrate good efficacy and tolerability of the DPP-4 inhibitors in patients with moderate or severe RI, thus opening a place for these therapies in the treatment of populations with T2DM and RI. Several of the DPP-4 inhibitors are already approved for use in patients with moderate or severe RI, including for those with end-stage renal disease. While discussing the advantages related to their common mechanism of action, this article also describes differences among the DPP-4 inhibitors (eg, related to their pharmacokinetic properties and the available clinical data). In conclusion, while initial data for these new therapies are promising, further experience is needed to fully assess the risk-benefit balance and clinical positioning of these agents in RI populations.

Review of treatment with zoledronic acid 4 mg

BackgroundZoledronic acid is a bisphosphonate indicated for the prevention of skeletal-related events in patients with advanced malignancies involving bone and treatment of hypercalcaemia of malignancy. According to data sheet Zometa...

Determination of Rivaroxaban in Human Plasma Samples

Rivaroxaban is one of the novel oral direct factor Xa inhibitors, which is effective in preventing thromboembolic complications at fixed doses (i.e., once daily), without the need for dose adjustment according to laboratory monitoring. Nearly 60% of rivaroxaban is cleared from circulation by glomerular filtration, 30% of which is excreted as active drug. Therefore, as renal elimination plays a pivotal role in the metabolism of this drug, impairment of renal function may be important during anticoagulation with rivaroxaban over long periods of time. The assessment of the anticoagulant effect/concentration of rivaroxaban may thus be useful in special patient populations such as in the elderly and eldest, during acute diseases with concurrent dehydration, before surgery, during bleeding or thrombotic episodes, or to verify adherence to therapy. Rivaroxaban prolongs prothrombin time in a dose-dependent, linear fashion. Activated partial thromboplastin time (APTT) is also prolonged, but in an exponential manner. Substantial differences in test results might be generated by different thromboplastin and APTT reagents. One-step prothrombin-induced clotting time assay is sensitive to low concentrations of rivaroxaban. Chromogenic substrate assays specific for factor Xa are also sensitive to rivaroxaban. Several initiatives are currently ongoing to standardize the various methods to determine rivaroxaban in human plasma samples, some of which will be summarized in this article along with the dose-dependent effects of rivaroxaban on relevant coagulation parameters. Therefore, although rivaroxaban prolongs all coagulation assays used to assess the anticoagulant effects of most anticoagulants, the most specific assay cannot be identified at present. Moreover, clinical trials are needed to determine the relationship of assay results with bleeding or thrombotic complications.

Management of myeloma-associated renal dysfunction in the era of novel therapies

Multiple myeloma (MM) is a plasma cell neoplasm often associated with renal impairment (RI), with myeloma cast nephropathy recognized as the most common cause. While RI is present in over 50% of MM patients at some point in their disease course, it is associated with higher tumor burden, more aggressive disease, diminished quality of life, development of complications and increased mortality. The introduction of novel therapies, including bortezomib, lenalidomide and thalidomide, has revolutionized the management of MM. They are now considered first-line therapies in induction, maintenance and salvage therapy for MM. In addition to their anti-MM effect, they can improve outcome in patients with RI, especially when combined, and bortezomib with dexamethasone may have a renal protective effect. This review focuses on the use of these agents in patients with MM and RI, and evaluates their efficacy, safety, need for dose adjustment and impact on RI.

Pharmacokinetics and Pharmacodynamics of Dabigatran Etexilate, an Oral Direct Thrombin Inhibitor, With Coadministration of Digoxin

This study evaluated the potential impact of concomitant digoxin on the pharmacokinetics and pharmacodynamics of dabigatran etexilate, a novel oral direct thrombin inhibitor. Healthy volunteers (n = 23) received 150 mg dabigatran etexilate twice daily on days 1 to 3 and once on day 4 in 1 period. Digoxin was given in another period as a loading dose of 0.5 mg early on day 1 and 0.25 mg in the evening of day 1 and on the mornings of days 2 to 4. In a third treatment period, dabigatran etexilate together with digoxin was given on days 1 to 4. Exposure to dabigatran was not significantly altered with concomitant digoxin-the maximum concentration (Cmax,ss ) and area under the concentration-time curve at steady state over 1 dosing interval (AUCτ,ss ) of dabigatran with and without digoxin were essentially unchanged. The pharmacokinetic profile of digoxin also remained unchanged in the presence of dabigatran etexilate. Dabigatran's anticoagulant effect, assessed by blood coagulation time assays, was not influenced by digoxin. Dabigatran etexilate and digoxin can be coadministered without the need for dose adjustment of either drug.