Physiologically-based pharmacokinetic modeling for mirabegron: a multi-elimination pathway mediated by cytochrome P450 3A4, uridine 5'-diphosphate-glucuronosyltransferase 2B7, and butyrylcholinesterase

1. This was the first study to construct a physiologically-based pharmacokinetic (PBPK) model for mirabegron which incorporates the overall elimination pathways of metabolism by cytochrome P450 (CYP) 3A4, uridine 5'-diphosphate-glucuronosyltransferase (UGT) 2B7, and butyrylcholinesterase (BChE) and renal excretion. The objective was to assess the risk of drug-drug interactions (DDIs) by estimating the contribution of each elimination pathway and simulating the magnitude of the DDIs with UGT2B7 inhibitors.

2. A PBPK model for mirabegron was constructed to reproduce the plasma concentration-time curves from a phase 1 study and the magnitude of the DDI with ketoconazole taking into account the overall elimination pathways. The PBPK model was subsequently verified using data from other DDI studies.

3. The constructed PBPK model estimated the contribution for each elimination pathway: 44% and 29% for CYP3A4 and UGT2B7 in the liver, 1.6% for UGT2B7 in the kidney, 3.2% for BChE in plasma, and 22% for renal excretion.

4. Co-administration of probenecid (an UGT2B7 inhibitor) or fluconazole (an UGT2B7 and CYP3A4 inhibitor) was predicted to increase area under the curve for mirabegron to 115% or 174%, respectively.

5. In conclusion, PBPK modeling and simulation revealed a low DDI risk for mirabegron following co-administration with BChE or UGT2B7 inhibitors.

     

Phase II Study of Panitumumab Monotherapy in Chemotherapy‐Naïve Frail or Elderly Patients with Unresectable RAS Wild‐Type Colorectal Cancer: OGSG 1602

Lessons Learned

• Panitumumab monotherapy showed favorable efficacy and feasibility in the treatment of frail or elderly patients with RAS wild‐type unresectable colorectal cancer.
• It is especially effective for left‐sided tumors; therefore, panitumumab as first‐line treatment could be an additional therapeutic option for frail elderly patients, particularly in those who are unsuitable for upfront oxaliplatin‐based or irinotecan‐based combination regimens.

BackgroundFirst‐line panitumumab monotherapy is expected to be well tolerated and improve survival in patients ineligible for intensive chemotherapy. However, its safety and efficacy in chemotherapy‐naïve frail or elderly patients with unresectable RAS wild‐type (WT) colorectal cancer (CRC) have not been studied. The aim of this phase II trial was to evaluate the efficacy and safety of panitumumab as first‐line treatment.MethodsWe conducted a multicenter phase II study on patients aged ≥76 years or ≥65 years considered unsuitable for intensive chemotherapy. Panitumumab 6 mg/kg of intravenous infusion was administered every 2 weeks. The primary endpoint was disease control rate (DCR). Secondary endpoints included progression‐free survival (PFS), overall survival (OS), response rate (RR), time to treatment failure (TTF), and incidence of grade 3 or 4 toxicities.ResultsThirty‐six patients (median age: 81 [range, 67–88] years) were enrolled between February 2017 and August 2018. Two patients were excluded from the analysis of efficacy: one from lack of image examination at baseline and the other from lack of a measurable lesion. Thirty‐three (91.6%) patients had a performance status (PS) of 0 or 1, whereas two (5.6%) patients and one (2.8%) patient had a PS of 2 and 3, respectively. Twenty‐eight patients (77.8%) had left‐sided CRC, whereas eight (22.2%) had right‐sided CRC. The RR was 50.0% (95% confidence interval [CI], 32.4–67.6), including three patients (8.8%) who had complete responses. A total of 26.5% had stable diseases, resulting in a DCR of 76.5% (90% CI, 61.5–87.7). The RR of patients with left‐ and right‐sided tumors was 65.4% (95% CI, 44.3–82.8) and 0.0% (95% CI, 0.0–36.9), respectively. Major grade 3 or 4 nonhematologic toxicities were rash (n = 6, 16.7%), hypomagnesemia (n = 4, 11.1%), fatigue (n = 3, 8.3%), paronychia (n = 2, 5.6%), and hyponatremia (n = 2, 5.6%). The only grade 3 hematologic toxicity was neutropenia (n = 1, 2.8%).ConclusionPanitumumab monotherapy showed favorable efficacy and feasibility in frail or elderly patients with RAS WT unresectable CRC. Survival analysis including OS, PFS, and TTF is currently in progress.     

Evaluation of apremilast,an oral phosphodiesterase 4 inhibitor,for refractory cutaneous dermatomyositis: A phase 1b clinical trial

Dermatomyositis, an idiopathic inflammatory myopathy, is characterized by cutaneous itchy manifestations, which are frequently refractory and recurrent even after intensive immunosuppressive treatments. To evaluate the effectiveness and safety of apremilast, an oral phosphodiesterase 4 inhibitor, in treating skin-dominant dermatomyositis in which myositis and interstitial lung disease are absent or in remission, we performed this prospective, single-arm, interventional study. A total of five Japanese patients (one male and four females, median [range] age, 64 [37–71] years) with refractory dermatomyositis-associated cutaneous manifestations were recruited and treated with a 12-week course of oral apremilast. Among five enrolled patients, three experienced diarrhea with full-dose apremilast (30 mg twice daily), two of whom withdrew from the study and recovered quickly afterwards. A total of three evaluable female patients (median [range] age, 65 [64–71] years) received apremilast treatment for 12 weeks. A 39.4% reduction from baseline Cutaneous Dermatomyositis Disease Area and Severity Index total activity score, but not the damage score, at week 12 was observed in all three patients. Visual analog scale of itching, and quality of life by Dermatology Life Quality Index were slightly improved in one and two apremilast-treated patients, respectively. As apremilast was effective, with expected and recoverable digestive adverse events (diarrhea), in patients with refractory and recurrent dermatomyositis-associated cutaneous manifestations in this first phase Ib study, it can be suggested as a possible treatment when aggressive immunosuppressive therapies with high-dose systemic corticosteroid and/or immunosuppressive agents for other manifestations, myositis, and interstitial lung disease, are not required.     

A rare case of pulmonary typical carcinoid with prominent acinic cell differentiation,resembling acinic cell carcinoma

We herein describe a rare case of low‐grade endobronchial tumor that exhibited two distinct features of typical carcinoid and acinic cell carcinoma (ACC) by immunohistochemical and ultrastructure study. ACC was suspected on transbronchial biopsy. The resected specimen showed that the tumor surface comprised an acinic cell component (40% of the tumor), and the central area comprised typical carcinoid (60% of the tumor). The acinic cell component was positive for chromogranin A, synaptophysin and alpha‐1‐antichymotrypsin. Additionally, this component showed focal apical membranous staining for DOG1 and weak positivity for BCL10 and SOX10. Conversely, the carcinoid component was negative for all proteins except for chromogranin A and synaptophysin. Electron microscopy indicated zymogen‐type granules (600–800 nm in diameter) in the acinic cell component, whereas neuroendocrine‐type granules (200–300 nm in diameter) were observed in the carcinoid component. Nuclear NR4A3 immunostaining, which is highly specific for ACC of the salivary gland, was negative in this case. We conclude that the pulmonary carcinoid tumor with true zymogen‐type granules could be seen but showed superficial similarities to ACC based on negative nuclear staining for NR4A3. Pulmonary carcinoids encompass a wide morphological spectrum and may exhibit prominent acinic cell differentiation.     

The anti-inflammatory effect of erythromycin in zymosan-induced peritonitis of mice.

The anti-inflammatory effect of erythromycin was investigated using zymosan-induced peritonitis in mice. When mice were given erythromycin 10 mg/kg/day po for 28 days, a marked suppression of inflammatory responses, including the reduced influx of leucocytes, plasma exudation and prostaglandin E2 synthesis, was observed. However, neither a 7-day treatment with erythromycin nor a 28-day treatment with clindamycin suppressed the response. The anti-inflammatory activity induced after a 28-day treatment with erythromycin was comparable to the anti-inflammatory effect conferred by a 2-day treatment with dexamethasone 40 microgram/mouse/day. Thus, these data confirm previous studies which show that erythromycin can exert an anti-inflammatory effect when used over long periods of time.     

Decline in estimated glomerular filtration rate is associated with risk of end-stage renal disease in type 2 diabetes with macroalbuminuria: an observational study from JDNCS

Background

There is increased interest in surrogate endpoints for clinical trials of chronic kidney disease.

Methods

In this nationwide observational study of 456 patients with type 2 diabetes and clinically suspected diabetic nephropathy followed for a median of 4.2 years, we evaluated the association between estimated glomerular filtration rate (eGFR) and albuminuria at baseline or during follow-up and risk of ESRD.

Results

Low eGFR (<60 mL/min/1.73 m²) and macroalbuminuria at enrollment were independently associated with risk of ESRD. In patients with macroalbuminuria, both ≤?50% change and ?50 to ?30% change in eGFR over 1 and 2 years were predictive of ESRD. The higher cut point (≥50% decline in eGFR) was more strongly predictive but less common. Remission of macroalbuminuria to normo-/microalbuminuria at 1 and 2 years was associated with a lower incidence of ESRD than no remission; however, it was not a determinant for ESRD independently of initial eGFR and initial protein-to-creatinine ratio.

Conclusion

These results suggest that a ≥30% decline in eGFR over 1 or 2 years adds prognostic information about risk for ESRD in patients with type 2 diabetes and macroalbuminuria, supporting the consideration of percentage decline in eGFR as a surrogate endpoint among macroalbuminuric cases in type 2 diabetes. On the other hand, our study suggests that additional analyses on the relationship between remission of macroalbuminuria and risk of ESRD are needed in type 2 diabetes.