Effect of the Wetting Agent Sodium Lauryl Sulfate on the Pharmacokinetics of Alectinib: Results From a Bioequivalence Study in Healthy Subjects

Morcos, Peter N.; Parrott, Neil; Banken, Ludger; Timpe, Carsten; Lindenberg, Marc; Guerini, Elena; Dall, Georgina; Bogman, Katrijn; Sturm, Carolina; Zeaiter, Ali; Martin‐Facklam, Meret; Phipps, Alex

doi:10.1002/cpdd.299

Cited by 9 publications

(9 citation statements)

References 45 publications

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“…The clinical pharmacokinetics (PK) of alectinib have been characterized in healthy subjects and in patients with ALK + NSCLC . Following single oral administration to patients with ALK + NSCLC, alectinib was absorbed with a median time to maximum plasma concentration (T max ) reached by 4 hours and a single‐dose apparent half‐life (t 1/2 ) of approximately 20 hours .…”

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confidence: 99%

“…The clinical pharmacokinetics (PK) of alectinib have been characterized in healthy subjects and in patients with ALK+ NSCLC. 14,[18][19][20][21][22][23] Following single oral administration to patients with ALK+ NSCLC, alectinib was absorbed with a median time to maximum plasma concentration (T max ) reached by 4 hours and a single-dose apparent half-life (t 1/2 ) of approximately 20 hours. 22 Following twice-daily administration of alectinib, plasma concentrations were associated with a low peak-to-trough ratio supporting a sustained exposure throughout the dosing interval.…”

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confidence: 99%

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Clinical Drug–Drug Interactions Through Cytochrome P450 3A (CYP3A) for the Selective ALK Inhibitor Alectinib

Morcos

Cleary

Guerini

et al. 2016

Clinical Pharm in Drug Dev

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The efficacy and safety of alectinib, a central nervous system-active and selective anaplastic lymphoma kinase (ALK) inhibitor, has been demonstrated in patients with ALK-positive (ALK+) non-small cell lung cancer (NSCLC) progressing on crizotinib. Alectinib is mainly metabolized by cytochrome P450 3A (CYP3A) to a major similarly active metabolite, M4. Alectinib and M4 show evidence of weak time-dependent inhibition and small induction of CYP3A in vitro. We present results from 3 fixed-sequence studies evaluating drug-drug interactions for alectinib through CYP3A. Studies NP28990 and NP29042 enrolled 17 and 24 healthy subjects, respectively, and investigated potent CYP3A inhibition with posaconazole and potent CYP3A induction through rifampin, respectively, on the single oral dose pharmacokinetics (PK) of alectinib. A substudy of the global phase 2 NP28673 study enrolled 15 patients with ALK+ NSCLC to determine the effect of multiple doses of alectinib on the single oral dose PK of midazolam, a sensitive substrate of CYP3A. Potent CYP3A inhibition or induction resulted in only minor effects on the combined exposure of alectinib and M4. Multiple doses of alectinib did not influence midazolam exposure. These results suggest that dose adjustments may not be needed when alectinib is coadministered with CYP3A inhibitors or inducers or for coadministered CYP3A substrates.

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confidence: 99%

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confidence: 99%

Clinical Drug–Drug Interactions Through Cytochrome P450 3A (CYP3A) for the Selective ALK Inhibitor Alectinib

Morcos

Cleary

Guerini

et al. 2016

Clinical Pharm in Drug Dev

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“…When the large amount of SLS, an anionic surfactant was orally administered, it can irritate the gastric mucosa and possibly lead to gastrointestinal adverse events. However, its small amounts have been frequently used in the development of oral pharmaceutical products due to its approval by FDA (Liu et al., 2016 ; Kim et al., 2016b ; Morcos et al., 2017 ). For choosing an appropriate hydrophilic polymer, the effect of the polymer on drug solubility in 1% SLS aqueous solution was investigated ( Supplementary Figure S2(B) ).…”

Section: Resultsmentioning

confidence: 99%

A novel solid self-nanoemulsifying drug delivery system (S-SNEDDS) for improved stability and oral bioavailability of an oily drug, 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol

et al. 2017

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To develop a novel solid self-nanoemulsifying drug delivery system (S-SNEDDS) for a water-insoluble oily drug, 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) with improved stability and oral bioavailability, numerous S-SNEDDS were prepared with surfactant, hydrophilic polymer, antioxidant, and calcium silicate (porous carrier) using the spray-drying method. Their physicochemical properties were evaluated using emulsion droplet size analysis, SEM and PXRD. Moreover, the solubility, dissolution, stability, and pharmacokinetics of the selected S-SNEDDS were assessed compared with the drug and a commercial soft capsule. Sodium lauryl sulfate (SLS) and hydroxypropyl methylcellulose (HPMC) with the highest drug solubility were selected as surfactant and hydrophilic polymer, respectively. Among the antioxidants tested, only butylated hydroxyanisole (BHA) could completely protect the drug from oxidative degradation. The S-SNEDDS composed of PLAG/SLS/HPMC/BHA/calcium silicate at a weight ratio of 1: 0.25: 0.1: 0.0002: 0.5 provided an emulsion droplet size of less than 300 nm. In this S-SNEDDS, the drug and other ingredients might exist in the pores of carrier and attach onto its surface. It considerably improved the drug stability (about 100 vs. 70%, 60 °C for 5 d) and dissolution (about 80 vs. 20% in 60 min) compared to the commercial soft capsule. Moreover, the S-SNEDDS gave higher AUC, C, and T values than the commercial soft capsule; in particular, the former improved the oral bioavailability of PLAG by about 3-fold. Our results suggested that this S-SNEDDS provided excellent stability and oral bioavailability of PLAG. Thus, this S-SNEDDS would be recommended as a powerful oral drug delivery system for an oily drug, PLAG.

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“…The validation process involved comparing the coincidence of predicted PK profiles with the observed ones. In addition, the models were verified by comparing the ratios between the predicted and observed AUC, C max , and C trough (Seto et al, 2013;Gadgeel et al, 2014;Xu et al, 2015a;Kurata et al, 2015;Morcos et al, 2017a;Morcos et al, 2017b;Morcos et al, 2017c;Shaw et al, 2017;Clark et al, 2019;Stypinski et al, 2020;Chen et al, 2021;Hibma et al, 2022;Huiping et al, 2022;Lin et al, 2022) following single dose and repeated doses. Furthermore, the models were further validated by comparing predicted and calculated PK profiles in the CSF.…”

Section: Physiologically Based Pharmacokinetic Model Verification And...mentioning

confidence: 99%

Prediction of trough concentration and ALK occupancy in plasma and cerebrospinal fluid using physiologically based pharmacokinetic modeling of crizotinib, alectinib, and lorlatinib

Li,

Liu,

Feng

et al. 2023

Front. Pharmacol.

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Backgrounds: Brain metastases occur in approximately 30% of patients with non-small-cell lung cancer (NSCLC). Therefore, the free drug concentration in cerebrospinal fluid (CSF) is strongly associated with the clinical efficacy.Purpose: The present study aimed to develop physiologically based pharmacokinetic (PBPK) models that can predict the steady-state trough concentration (Ctrough) in plasma and CSF, as well as anaplastic lymphoma kinase (ALK) occupancy (AO), for three inhibitors: crizotinib (CRI), alectinib (ALE), and lorlatinib (LOR).Methods: To achieve this, population PBPK models were successfully developed and validated using multiple clinical pharmacokinetics (PK) and drug–drug interaction (DDI) studies, both in healthy subjects and patients.Results: The prediction-to-observation ratios for plasma AUC, Cmax, and Ctrough in heathy subjects and patients ranged between 0.5 and 2.0. In addition, PK profiles of CRI, ALE, and LOR in CSF aligned well with observed data. Moreover, the AUC and Cmax ratios of the three inhibitors when co-administered with CYP3A4 inhibitors/inducers also matched with clinically observed values. Utilizing PK thresholds for effective plasma Ctrough and AO values on wild-type and four ALK mutations in plasma and CSF, PBPK models were then combined with the mean and 95% confidence interval to predict optimal dosing regimens.Conclusions: Overall, these PBPK models provide valuable insights into determining appropriate dosing regimens for the three ALK inhibitors, understanding their effectiveness in brain metastasis therapy, and analyzing the underlying mechanisms of on-target resistance.

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Effect of the Wetting Agent Sodium Lauryl Sulfate on the Pharmacokinetics of Alectinib: Results From a Bioequivalence Study in Healthy Subjects

Cited by 9 publications

References 45 publications

Clinical Drug–Drug Interactions Through Cytochrome P450 3A (CYP3A) for the Selective ALK Inhibitor Alectinib

Clinical Drug–Drug Interactions Through Cytochrome P450 3A (CYP3A) for the Selective ALK Inhibitor Alectinib

A novel solid self-nanoemulsifying drug delivery system (S-SNEDDS) for improved stability and oral bioavailability of an oily drug, 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol

Prediction of trough concentration and ALK occupancy in plasma and cerebrospinal fluid using physiologically based pharmacokinetic modeling of crizotinib, alectinib, and lorlatinib

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