Population pharmacokinetics of sonidegib (LDE225), an oral inhibitor of hedgehog pathway signaling, in healthy subjects and in patients with advanced solid tumors

Goel, Varun; Hurh, Eunju; Stein, Andrew M.; Nedelman, Jerry; Zhou, Jocelyn; Chiparus, Ovidiu; Huang, Pai-Hsi; Gogov, Sven; Sellami, Dalila

doi:10.1007/s00280-016-2982-1

Cited by 36 publications

(41 citation statements)

References 14 publications

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“…Previously published population PK and exposure‐toxicity models of sonidegib were used to simulate (n = 100) scenarios of taking sonidegib in different ways with respect to food . It was known that sonidegib had a 5‐ to 7‐fold increase in exposure with a high‐fat, high‐caloric meal.…”

Section: Methodsmentioning

confidence: 99%

“…It was known that sonidegib had a 5‐ to 7‐fold increase in exposure with a high‐fat, high‐caloric meal. Briefly, a 2‐compartment model with first‐order absorption with lag‐time, linear elimination, and bioavailability that increased by 5.74‐fold in fed condition was used to simulate the steady state trough plasma concentration on cycle 2 day 1 of sonidegib therapy . This simulated PK metric was used in an exposure‐toxicity model to drive the probability of developing a grade 3/4 creatine kinase (CK) elevation according to Equations and ,

log [\frac{π false(normalx false)}{π false(normalx false) + 1}] = β_{0} + β_{1} \cdot {normalC}_{trueprefixmin} / 100 + β_{2} \cdot Sex

π false(normalx false) = \frac{exp (β_{0} + β_{1} \cdot C_{min} + β_{2} \cdot Sex)}{1 + exp (β_{0} + β_{1} \cdot C_{min} + β_{2} \cdot Sex)}

where π(x) is the probability of developing grade 3/4 CK elevation, β 0 , β 1 , and β 2 are the intercept (−2.58) and slopes (0.10 for C min and −0.92 for female) in the logistic regression, and C min is the steady‐state trough plasma concentration (ng/mL) on cycle 2 day 1.…”

Section: Methodsmentioning

confidence: 99%

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To Take or Not to Take With Meals? Unraveling Issues Related to Food Effects Labeling for Oral Antineoplastic Drugs

Deng

Brar

Lesko

2017

Clinical Pharm in Drug Dev

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There has been controversy regarding whether bioavailability of certain oral oncology drugs should be maximized by taking these medications with food, irrespective of label instructions in the dosing and administration section. To provide insight into this controversy, we conducted an in-depth analysis for oral antineoplastic drugs approved by the Food and Drug Administration in 2000-2016 and identified important issues influencing food labeling decisions. Furthermore, a case study involving sonidegib, a drug approved for locally advanced basal cell carcinoma with a significant food effect on exposure, was used to demonstrate the consequences of failure to adhere to food label recommendations using drug-specific population pharmacokinetic and exposure-toxicity models. In 2000-2009, 80% (4 out of 5) of all approved oral antineoplastics with increased bioavailability in the fed state were labeled as "take on empty stomach." In contrast, we found that in 2010-2016 there is a greater diversity in food recommendations for drugs with increased bioavailability in the fed state. Currently, many oral oncology drugs are given with food to maximize their bioavailability; however, as seen from our case study of sonidegib, failure to fully adhere to label recommendations to either take with food or not could lead to adverse consequences in terms of safety and efficacy.

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Section: Methodsmentioning

confidence: 99%

log [\frac{π false(normalx false)}{π false(normalx false) + 1}] = β_{0} + β_{1} \cdot {normalC}_{trueprefixmin} / 100 + β_{2} \cdot Sex

π false(normalx false) = \frac{exp (β_{0} + β_{1} \cdot C_{min} + β_{2} \cdot Sex)}{1 + exp (β_{0} + β_{1} \cdot C_{min} + β_{2} \cdot Sex)}

Section: Methodsmentioning

confidence: 99%

To Take or Not to Take With Meals? Unraveling Issues Related to Food Effects Labeling for Oral Antineoplastic Drugs

Deng

Brar

Lesko

2017

Clinical Pharm in Drug Dev

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“…Sonidegib has multiple pharmacokinetic properties that make it an effective therapeutic agent 47. It is highly bound to plasma proteins (over 99%) in humans.…”

Section: Metabolic Profiles and Pharmacokinetics Of Sonidegibmentioning

confidence: 99%

Sonidegib: mechanism of action, pharmacology, and clinical utility for advanced basal cell carcinomas

Jain¹,

Song²,

Xie³

2017

OTT

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The Hedgehog (Hh) pathway is critical for cell differentiation, tissue polarity, and stem cell maintenance during embryonic development, but is silent in adult tissues under normal conditions. However, aberrant Hh signaling activation has been implicated in the development and promotion of certain types of cancer, including basal cell carcinoma (BCC), medulloblastoma, and gastrointestinal cancers. In 2015, the US Food and Drug Administration (FDA) approved sonidegib, a smoothened (SMO) antagonist, for treatment of advanced BCC (aBCC) after a successful Phase II clinical trial. Sonidegib, also named Odomzo, is the second Hh signaling inhibitor approved by the FDA to treat BCCs following approval of the first SMO antagonist vismodegib in 2012. What are the major features of sonidegib (mechanism of action; metabolic profiles, clinical efficacy, safety, and tolerability profiles)? Will the sonidegib experience help other clinical trials using Hh signaling inhibitors in the future? In this review, we will summarize current understanding of BCCs and Hh signaling. We will focus on sonidegib and its use in the clinic, and we will discuss ways to improve its clinical application in cancer therapeutics.

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“…The investigators were unable to establish a relationship between muscle cramps and elevated creatine kinase, as many patients experienced muscle cramps with normal serum levels of creatine kinase while others had no muscle cramps and elevated levels of creatine kinase [20]. Sonidegib's high binding capacity to serum proteins may explain its relatively long half-life (29.6 days) [21]. Sonidegib has a maximum serum concentration (C max ) of 1030 ng/ml with a time to achieve this concentration (t max ) of 2-4 h. Sonidegib reaches steady state roughly 4 months after an initial dose and has a volume of distribution of around 2500 L. CYP3A is the main enzyme responsible for metabolizing sonidegib and drug interactions with this hepatic enzyme can potentially increase the risk for muscle spasms.…”

mentioning

confidence: 99%

Treatment of Advanced Basal Cell Carcinoma with Sonidegib: Perspective from the 30-Month Update of the BOLT Trial

Chen¹,

Aria²,

Silapunt³

et al. 2017

Future Oncol.

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Sonidegib, a hedgehog pathway inhibitor, was approved by the US FDA for the treatment of locally advanced basal cell carcinoma which cannot be readily treated with surgery or radiotherapy. The pharmacology and pharmacokinetics of sonidegib will be discussed in this review. Additionally, an in-depth analysis of the BOLT trial and data from the 30-month update will be included. This will serve as an update to a previously published article which reported the 12-month update of the BOLT trial. BackgroundBasal cell carcinoma (BCC) is the most common skin cancer in humans. Annually, there are 2.8 million cases that result in approximately 3000 deaths [1]. The use of surgical excision for the treatment of BCC results in a 5-year cure rate close to 90% [2,3]. The 5-year recurrence rate decreases to 0.7-2.4% when Mohs micrographic surgery (MMS) is performed [4][5][6][7]. Alternative nonsurgical approaches include cryotherapy, electrodesiccation and curettage, photodynamic therapy, radiation, or topical agents such as imiquimod or 5-fluorouracil. These options usually confer a lower cure rate and lack confirmation of tumor clearance on histology. Although metastasis of BCC has a very low incidence of 0.0028-0.

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Population pharmacokinetics of sonidegib (LDE225), an oral inhibitor of hedgehog pathway signaling, in healthy subjects and in patients with advanced solid tumors

Abstract: No dose adjustment is needed for mild hepatic impairment, mild and moderate renal impairment, age, weight, gender, or ethnicity. This population PK model adequately characterizes sonidegib PK characteristics and can be used for various simulations and applications.

Cited by 36 publications

References 14 publications

To Take or Not to Take With Meals? Unraveling Issues Related to Food Effects Labeling for Oral Antineoplastic Drugs

To Take or Not to Take With Meals? Unraveling Issues Related to Food Effects Labeling for Oral Antineoplastic Drugs

Sonidegib: mechanism of action, pharmacology, and clinical utility for advanced basal cell carcinomas

Treatment of Advanced Basal Cell Carcinoma with Sonidegib: Perspective from the 30-Month Update of the BOLT Trial

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