Pharmacokinetic and pharmacodynamic comparison of subcutaneous<i>versus</i>intramuscular leuprolide acetate formulations in male subjects

Saltzstein, Daniel R.; Shore, Neal D.; Moul, Judd W.; Chu, Franklin; Concepcion, Raoul S.; Motte, Stephan de la; McLane, John A.; Atkinson, Stuart; Yang, Alex; Crawford, E. David

doi:10.1177/1756287217738150

Cited by 19 publications

(16 citation statements)

References 29 publications

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“…Although direct statistical comparisons of PK parameters were not conducted as the populations were different in each trial, the overall PK profiles from each study (“Bilaterally orchiectomized male study,” pivotal trials, and “PKPD study”) were comparable. The observation for serum LA level in bilaterally orchiectomized males is consistent with the Gel‐LA clinical study in healthy subjects (“PKPD study”), where duration of measurable and adequate serum LA levels similarly ranged from 42‐56 days after dosing (Table 2, Figure 2B), exceeding the 1‐month dosing period 21 …”

Section: Discussionsupporting

confidence: 83%

“…In pivotal trials, clinical efficacy of the four doses of Gel‐LA demonstrated continuous suppression of T to concentrations ≤20 ng/dL through achievement of median serum levels of LA above 0.05 ng/mL (assay lower limit of quantification [LLOQ]: 0.1 ng/mL for 1‐ and 3‐month and 0.05 ng/mL for 4‐ and 6‐month formulations) 16‐20 . The pharmacokinetics (PK) of a single dose of Gel‐LA have also previously been described in healthy subjects (“PKPD study”) 21 …”

Section: Introductionmentioning

confidence: 98%

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Subcutaneous in situ gel delivered leuprolide acetate's consistent and prolonged drug delivery maintains effective testosterone suppression independent of age and weight in men with prostate cancer

et al. 2020

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Objectives:To assess the impact of patient age and weight on the pharmacokinetics (PK), testosterone (T) suppression and safety from four fixed dosing regimens (7.5, 22.5, 30, or 45 mg for 1-, 3-, 4-, or 6-months, respectively) of subcutaneous in situ gel delivered leuprolide acetate (Gel-LA) injected via the ATRIGEL Delivery System in patients with prostate cancer (PCa). Patients and methods:Two patient populations were specified for analysis: a small cohort of surgically castrated PCa patients and a large, pooled population of PCa patients from four pivotal trials of Gel-LA. Two separate analyses of the impact of age and weight on study endpoints were conducted: (1) PK and safety of a single monthly dose of Gel-LA in a Phase 1 study with PCa patients who had undergone bilateral surgical orchiectomy ("Bilaterally orchiectomized male study"); (2) PK/pharmacodynamic (PD) effects and safety using pooled data from four pivotal trials assessing 1-, 3-, 4-, and 6-month dosing of Gel-LA in patients with advanced PCa, stratified by age and body weight (pivotal trials).Results: Eight orchiectomized patients from the "Bilaterally orchiectomized male study" and 438 patients from the pivotal trials were included in the analyses. Age and body weight did not appear to affect the PK results in the orchiectomized patient population. Pooled pivotal trial data showed that serum T levels did not appear to be influenced by age or weight; ≥90% of patients across all age groups and ≥92% of patients across all weight groups achieved T ≤ 50 ng/dL by week 4. Median T levels for castration (T ≤ 50 ng/dL) were maintained from week 3 until the end of the study and all subgroups achieved median T ≤ 20 ng/dL by week 4. Patients from the orchiectomized patient study did not report any serious treatment-related adverse events (AEs) and there were no AE-related withdrawals from the study. The most common AEs were hot flashes and injection site events. The safety profiles from pivotal trials have been previously described and, as expected, were consistent with known effects of LHRH agonist therapy and suppression of T levels. | 65 RENZULLI Et aL.

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Section: Discussionsupporting

confidence: 83%

Section: Introductionmentioning

confidence: 98%

Subcutaneous in situ gel delivered leuprolide acetate's consistent and prolonged drug delivery maintains effective testosterone suppression independent of age and weight in men with prostate cancer

et al. 2020

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“…In a phase 1 study of 1-month doses of IM-LA and SC-LA, serum LA levels in the SC-LA arm remained above the limit of quantitation (defined as effective) for 10−20 days longer than IM-LA. These PK differences resulted in very different PD profiles, with SC-LA suppressing LH and maintaining median T levels at castrate level for a longer period (at least 56 days vs. 35 days in SC-LA and IM-LA arms, respectively) [37]. These outcomes are likely attributed to differences in the controlled-release technologies and the data challenge the commonly accepted position that ADT therapies are interchangeable.…”

Section: Current Armamentarium Of Drugs Targeting Reduction In Testosmentioning

confidence: 99%

Androgen-targeted therapy in men with prostate cancer: evolving practice and future considerations

Crawford

Heidenreich

Lawrentschuk

et al. 2018

Prostate Cancer Prostatic Dis

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Modern assay technologies reveal that bilateral orchiectomy results in a serum T level of approximately 15 ng/dL as compared to the historical definition of castration of T < 50 ng/dL. Evidence shows that lowering T levels to <20 ng/dL improves patient survival and delays disease progression. Routine monitoring of T in addition to prostate-specific antigen throughout treatment is important to ensure continuing efficacy of T suppression. New drugs that inhibit androgen signaling in combination with traditional ADT suppress T activity to near zero and have significantly improved patient survival. When personalizing ADT regimens physicians should consider a number of factors including initiation and duration of ADT, monitoring of T levels and PSA, the possibility of switching monotherapies if a patient does not achieve adequate T suppression, and consideration of intermittent vs. continuous ADT according to patients' lifestyles, comorbidities, risk factors and tolerance to treatment.

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“…Prostate cancer, the second most common type of cancer in men (14%), is the main cause of death among cancer patients and is the sixth cause of cancer‐related death (6%) worldwide . Suppression of the serum testosterone to concentrations below the castration levels (<50 ng/dL) is the standard palliative treatment method in patients with advanced prostate cancer . Leuprolide acetate (LA) and triptorelin acetate (TA) (Fig.…”

Section: Introductionmentioning

confidence: 99%

“…HPLC methods and quantification by radioimmunoassay and MS/MS detections are analytical methods, which have been developed for quantification and pharmacokinetic study of LA. Moreover, quantification of TA has been developed by LC–MS/MS .…”

Section: Introductionmentioning

confidence: 99%

Quantification of controlled release leuprolide and triptorelin in rabbit plasma using electromembrane extraction coupled with HPLC–UV

2019

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An electromembrane extraction followed by HPLC-UV technique was developed and validated for quantification of leuprolide and triptorelin in rabbit plasma. The influencing parameters on the extraction efficiency were optimized using experimental design methodology. The optimized conditions were found to be; supported liquid membrane: a mixture of 1-octanol and 2-ethyl hexanol (1:1) containing 10% v/v di(2-ethylhexyl) phosphate, applied voltage: 5 V, extraction time: 5 min, pH of the donor phase: 4.5 and pH of the acceptor phase: 1.0. The optimized method was validated for linearity, intraday and interday precision, and accuracy in rabbit plasma. The range of quantification for both peptides was 0.5-1000 ng/mL with regression coefficients higher than 0.994. Relative recoveries of leuprolide and triptorelin were found to be 80.3 and 75.5%, respectively. Limits of quantification and detection for both peptides were found to be 0.5 and 0.15 ng/mL, respectively. The validated method was successfully applied to pharmacokinetic study of the 1-month depot formulations of each peptide after subcutaneous administration to rabbits.

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Pharmacokinetic and pharmacodynamic comparison of subcutaneousversusintramuscular leuprolide acetate formulations in male subjects

Cited by 19 publications

References 29 publications

Subcutaneous in situ gel delivered leuprolide acetate's consistent and prolonged drug delivery maintains effective testosterone suppression independent of age and weight in men with prostate cancer

Subcutaneous in situ gel delivered leuprolide acetate's consistent and prolonged drug delivery maintains effective testosterone suppression independent of age and weight in men with prostate cancer

Androgen-targeted therapy in men with prostate cancer: evolving practice and future considerations

Quantification of controlled release leuprolide and triptorelin in rabbit plasma using electromembrane extraction coupled with HPLC–UV

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