Systemic bioavailability of hydrofluoroalkane (HFA) formulations of fluticasone/salmeterol in healthy volunteers via pMDI alone and spacer

Karine L. Clearie, Peter A. Williamson, Sriram Vaidyanathan, Jeannine Du Bois, Haylene Nell, Brian J. Lipworth

    Research output: Contribution to journalArticle

    14 Citations (Scopus)

    Abstract

    Seretide (GlaxoSmithKline, UK) is a combination inhaler which contains both fluticasone (FP) and salmeterol (SM).

    A generic fluticasone/salmeterol (FP/SM) combination inhaler (Neolab, UK) has recently been developed.

    Determination of therapeutic equivalence is essential in the development of generic products.

    WHAT THIS STUDY ADDS

    This paper determines that in vitro fine particle dose may not predict pharmacokinetic and systemic pharmacodynamic outcomes.

    This paper shows that the generic and reference products were equivalent in terms of FP, but not SM pharmacokinetics.

    No significant differences were found between generic and reference products in terms of either adrenal suppression or hypokalaemia.

    AIM

    To compare a test version of HFA fluticasone/salmeterol (FP/SM) combination inhaler (Neolab, UK) with the reference product Seretide (GlaxoSmithKline, UK).

    METHODS

    An in vitro Anderson cascade impactor was used to compare the fine particle dose (< 4.7 mu m). Two separate randomized cross-over studies were performed to compare the systemic bioavailability of test vs. reference (T vs. R) formulations of FP/SM 250/25 mu g pMDI in healthy volunteers. In study 1 blood pharmacokinetic analysis using oral charcoal block was performed over 24 h following a single dose of four puffs via pMDI alone. In study 2 systemic bioactivity was measured following single doses of four and eight puffs via a spacer device: serum potassium (K+) to reflect SM, and overnight urinary cortisol : creatinine (OUCC) for FP. An early pharmacokinetic profile was also assessed over 120 min.

    RESULTS

    The in vitro fine particle dose was similar for test vs. reference pMDI alone and via spacer. The results of both studies were consistent: No significant differences between formulations were seen in terms of FP kinetics. Analysis of SM kinetics revealed superiority of the test product. No significant dose-response or difference in T : R ratio was noted for OUCC. Fall in K+ revealed a significant dose-response with a non-significant T : R ratio.

    CONCLUSIONS

    The in vitro fine particle dose may not predict pharmacokinetic and systemic pharmacodynamic outcomes. Single dosing studies with fluticasone/salmeterol 250/25 mu g via pMDI or with spacer showed pharmacokinetic equivalence with FP, but not SM. No significant difference between formulations was seen with either adrenal suppression or hypokalaemia.

    Original languageEnglish
    Pages (from-to)637-644
    Number of pages8
    JournalBritish Journal of Clinical Pharmacology
    Volume69
    Issue number6
    DOIs
    Publication statusPublished - Jun 2010

    Keywords

    • Fluticasone
    • Salmeterol
    • HFA
    • Pharmacokinetics
    • Bronchodilator subsensitivity
    • Asthmatic patients
    • Inhaled corticosteroids
    • MU-G
    • Propionate
    • Salmeterol
    • Pharmacokinetics
    • Responses
    • Eformoterol
    • Salbutamol

    Cite this

    Clearie, Karine L. ; Williamson, Peter A. ; Vaidyanathan, Sriram ; Du Bois, Jeannine ; Nell, Haylene ; Lipworth, Brian J. / Systemic bioavailability of hydrofluoroalkane (HFA) formulations of fluticasone/salmeterol in healthy volunteers via pMDI alone and spacer. In: British Journal of Clinical Pharmacology. 2010 ; Vol. 69, No. 6. pp. 637-644.
    @article{c888e4580c1440aab68b5f71bcf416e0,
    title = "Systemic bioavailability of hydrofluoroalkane (HFA) formulations of fluticasone/salmeterol in healthy volunteers via pMDI alone and spacer",
    abstract = "Seretide (GlaxoSmithKline, UK) is a combination inhaler which contains both fluticasone (FP) and salmeterol (SM). A generic fluticasone/salmeterol (FP/SM) combination inhaler (Neolab, UK) has recently been developed. Determination of therapeutic equivalence is essential in the development of generic products. WHAT THIS STUDY ADDS This paper determines that in vitro fine particle dose may not predict pharmacokinetic and systemic pharmacodynamic outcomes. This paper shows that the generic and reference products were equivalent in terms of FP, but not SM pharmacokinetics. No significant differences were found between generic and reference products in terms of either adrenal suppression or hypokalaemia. AIM To compare a test version of HFA fluticasone/salmeterol (FP/SM) combination inhaler (Neolab, UK) with the reference product Seretide (GlaxoSmithKline, UK). METHODS An in vitro Anderson cascade impactor was used to compare the fine particle dose (< 4.7 mu m). Two separate randomized cross-over studies were performed to compare the systemic bioavailability of test vs. reference (T vs. R) formulations of FP/SM 250/25 mu g pMDI in healthy volunteers. In study 1 blood pharmacokinetic analysis using oral charcoal block was performed over 24 h following a single dose of four puffs via pMDI alone. In study 2 systemic bioactivity was measured following single doses of four and eight puffs via a spacer device: serum potassium (K+) to reflect SM, and overnight urinary cortisol : creatinine (OUCC) for FP. An early pharmacokinetic profile was also assessed over 120 min. RESULTS The in vitro fine particle dose was similar for test vs. reference pMDI alone and via spacer. The results of both studies were consistent: No significant differences between formulations were seen in terms of FP kinetics. Analysis of SM kinetics revealed superiority of the test product. No significant dose-response or difference in T : R ratio was noted for OUCC. Fall in K+ revealed a significant dose-response with a non-significant T : R ratio. CONCLUSIONS The in vitro fine particle dose may not predict pharmacokinetic and systemic pharmacodynamic outcomes. Single dosing studies with fluticasone/salmeterol 250/25 mu g via pMDI or with spacer showed pharmacokinetic equivalence with FP, but not SM. No significant difference between formulations was seen with either adrenal suppression or hypokalaemia.",
    keywords = "Fluticasone, Salmeterol, HFA, Pharmacokinetics, Bronchodilator subsensitivity, Asthmatic patients, Inhaled corticosteroids, MU-G, Propionate, Salmeterol, Pharmacokinetics, Responses, Eformoterol, Salbutamol",
    author = "Clearie, {Karine L.} and Williamson, {Peter A.} and Sriram Vaidyanathan and {Du Bois}, Jeannine and Haylene Nell and Lipworth, {Brian J.}",
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    Systemic bioavailability of hydrofluoroalkane (HFA) formulations of fluticasone/salmeterol in healthy volunteers via pMDI alone and spacer. / Clearie, Karine L.; Williamson, Peter A.; Vaidyanathan, Sriram; Du Bois, Jeannine; Nell, Haylene; Lipworth, Brian J.

    In: British Journal of Clinical Pharmacology, Vol. 69, No. 6, 06.2010, p. 637-644.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Systemic bioavailability of hydrofluoroalkane (HFA) formulations of fluticasone/salmeterol in healthy volunteers via pMDI alone and spacer

    AU - Clearie, Karine L.

    AU - Williamson, Peter A.

    AU - Vaidyanathan, Sriram

    AU - Du Bois, Jeannine

    AU - Nell, Haylene

    AU - Lipworth, Brian J.

    PY - 2010/6

    Y1 - 2010/6

    N2 - Seretide (GlaxoSmithKline, UK) is a combination inhaler which contains both fluticasone (FP) and salmeterol (SM). A generic fluticasone/salmeterol (FP/SM) combination inhaler (Neolab, UK) has recently been developed. Determination of therapeutic equivalence is essential in the development of generic products. WHAT THIS STUDY ADDS This paper determines that in vitro fine particle dose may not predict pharmacokinetic and systemic pharmacodynamic outcomes. This paper shows that the generic and reference products were equivalent in terms of FP, but not SM pharmacokinetics. No significant differences were found between generic and reference products in terms of either adrenal suppression or hypokalaemia. AIM To compare a test version of HFA fluticasone/salmeterol (FP/SM) combination inhaler (Neolab, UK) with the reference product Seretide (GlaxoSmithKline, UK). METHODS An in vitro Anderson cascade impactor was used to compare the fine particle dose (< 4.7 mu m). Two separate randomized cross-over studies were performed to compare the systemic bioavailability of test vs. reference (T vs. R) formulations of FP/SM 250/25 mu g pMDI in healthy volunteers. In study 1 blood pharmacokinetic analysis using oral charcoal block was performed over 24 h following a single dose of four puffs via pMDI alone. In study 2 systemic bioactivity was measured following single doses of four and eight puffs via a spacer device: serum potassium (K+) to reflect SM, and overnight urinary cortisol : creatinine (OUCC) for FP. An early pharmacokinetic profile was also assessed over 120 min. RESULTS The in vitro fine particle dose was similar for test vs. reference pMDI alone and via spacer. The results of both studies were consistent: No significant differences between formulations were seen in terms of FP kinetics. Analysis of SM kinetics revealed superiority of the test product. No significant dose-response or difference in T : R ratio was noted for OUCC. Fall in K+ revealed a significant dose-response with a non-significant T : R ratio. CONCLUSIONS The in vitro fine particle dose may not predict pharmacokinetic and systemic pharmacodynamic outcomes. Single dosing studies with fluticasone/salmeterol 250/25 mu g via pMDI or with spacer showed pharmacokinetic equivalence with FP, but not SM. No significant difference between formulations was seen with either adrenal suppression or hypokalaemia.

    AB - Seretide (GlaxoSmithKline, UK) is a combination inhaler which contains both fluticasone (FP) and salmeterol (SM). A generic fluticasone/salmeterol (FP/SM) combination inhaler (Neolab, UK) has recently been developed. Determination of therapeutic equivalence is essential in the development of generic products. WHAT THIS STUDY ADDS This paper determines that in vitro fine particle dose may not predict pharmacokinetic and systemic pharmacodynamic outcomes. This paper shows that the generic and reference products were equivalent in terms of FP, but not SM pharmacokinetics. No significant differences were found between generic and reference products in terms of either adrenal suppression or hypokalaemia. AIM To compare a test version of HFA fluticasone/salmeterol (FP/SM) combination inhaler (Neolab, UK) with the reference product Seretide (GlaxoSmithKline, UK). METHODS An in vitro Anderson cascade impactor was used to compare the fine particle dose (< 4.7 mu m). Two separate randomized cross-over studies were performed to compare the systemic bioavailability of test vs. reference (T vs. R) formulations of FP/SM 250/25 mu g pMDI in healthy volunteers. In study 1 blood pharmacokinetic analysis using oral charcoal block was performed over 24 h following a single dose of four puffs via pMDI alone. In study 2 systemic bioactivity was measured following single doses of four and eight puffs via a spacer device: serum potassium (K+) to reflect SM, and overnight urinary cortisol : creatinine (OUCC) for FP. An early pharmacokinetic profile was also assessed over 120 min. RESULTS The in vitro fine particle dose was similar for test vs. reference pMDI alone and via spacer. The results of both studies were consistent: No significant differences between formulations were seen in terms of FP kinetics. Analysis of SM kinetics revealed superiority of the test product. No significant dose-response or difference in T : R ratio was noted for OUCC. Fall in K+ revealed a significant dose-response with a non-significant T : R ratio. CONCLUSIONS The in vitro fine particle dose may not predict pharmacokinetic and systemic pharmacodynamic outcomes. Single dosing studies with fluticasone/salmeterol 250/25 mu g via pMDI or with spacer showed pharmacokinetic equivalence with FP, but not SM. No significant difference between formulations was seen with either adrenal suppression or hypokalaemia.

    KW - Fluticasone

    KW - Salmeterol

    KW - HFA

    KW - Pharmacokinetics

    KW - Bronchodilator subsensitivity

    KW - Asthmatic patients

    KW - Inhaled corticosteroids

    KW - MU-G

    KW - Propionate

    KW - Salmeterol

    KW - Pharmacokinetics

    KW - Responses

    KW - Eformoterol

    KW - Salbutamol

    U2 - 10.1111/j.1365-2125.2010.03655.x

    DO - 10.1111/j.1365-2125.2010.03655.x

    M3 - Article

    VL - 69

    SP - 637

    EP - 644

    JO - British Journal of Clinical Pharmacology

    JF - British Journal of Clinical Pharmacology

    SN - 0306-5251

    IS - 6

    ER -