Pharmacokinetics and Bioavailability Study of Lasolvan Hard Capsules and Effervescent Tablets in Healthy Volunteers

Study Overview
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Brief Summary
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To characterise pharmacokinetics and assess the relative bioavailability of two new oral formulations of ambroxol hydrochloride as Lasolvan® prolonged-release hard capsules 75 mg and Lasolvan® effervescent tablets 60 mg compared to Lasolvan® tablets 30 mg

Official Title
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An Open-label, Randomised, Multiple-dose, Three-period Crossover Study in Healthy Male and Female Volunteers to Characterise Pharmacokinetics and Assess the Relative Bioavailability of Two New Oral Formulations of Ambroxol Hydrochloride as Lasolvan® Prolonged-release Hard Capsules 75 mg and Lasolvan® Effervescent Tablets 60 mg Compared to Lasolvan® Tablets 30 mg.

Conditions
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Healthy

Intervention / Treatment
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* Drug: Lasolvan tablet
* Drug: Lasolvan tablet
* Drug: Lasolvan tablet
* Drug: Lasolvan tablet
* Drug: Lasolvan effervescent tablet
* Drug: Lasolvan effervescent tablet
* Drug: Lasolvan effervescent tablet
* Drug: Lasolvan prolonged-release hard capsule
* Drug: Lasolvan prolonged-release hard capsule
* Drug: Lasolvan prolonged-released capsules
* Drug: Lasolvan tablet
* Drug: Lasolvan tablet
* Drug: Lasolvan prolonged-release hard capsule
* Drug: Lasolvan effervescent tablet
* Drug: Lasolvan prolonged-release hard capsule
* Drug: Lasolvan prolonged-release hard capsule
* Drug: Lasolvan effervescent tablet
* Drug: Lasolvan effervescent tablet


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Given written informed consent for participation in the study. Male and female subjects aged 18-45, inclusive. Body mass index by Quetelet 18.50 - 24.99 kg/m2, inclusive. Judged by the investigator to be in good health as documented by the medical history, physical examination (including but may not be limited to an evaluation of the cardiovascular, gastrointestinal, and renal systems), vital signs assessments, 12-lead electrocardiogram (ECG), clinical laboratory assessments, and by general observations. Any abnormalities outside normal ranges for any clinical testing (laboratory tests, ECG, vital signs) can be repeated at the discretion of the investigator and judged to be not clinically significant for the study participation. Female subjects of childbearing potential who agree on using double-barrier contraception during the study. If female is postmenopausal (no menses for at least 1 year) or surgically sterile (bilateral tubal ligation, bilateral oophorectomy, or hysterectomy) she will be exempt from the requirement. In case of using oral contraceptives, they should be withdrawn at least 2 months before the study. Male subjects who agree on using effective contraception during the study (barrier contraceptive methods). Exclusion criteria: Known hypersensitivity to ambroxol hydrochloride, or other constituents of the test and reference products. Known rare hereditary conditions (Stevens-Johnson syndrome, toxic epidermal necrolysis, galactose intolerance, Lapp-lactase deficiency, glucose-galactose malabsorption). Pregnancy or breastfeeding. Chronic hepatic, renal, cardiovascular, respiratory, gastrointestinal, neuroendocrine diseases and blood disorders. Positive results of blood tests for current infections (HIV, syphilis, hepatitis B or C). Surgery of gastro-intestinal tract (except of appendectomy) within the past 8 weeks. Acute infections occurred within 4 weeks before inclusion into the study. Regular drug intake within 2 weeks before inclusion into the study. Intake of systemic drugs known to affect cytochrome P450 system (induce or inhibit) within 4 weeks before inclusion into the study. Blood donation (greater or equal 450 ml) within 2 months before inclusion into the study. Alcohol intake greater than or equal to 10 units of alcohol per week (1 unit of alcohol equals one 50 ml single measure of whisky (ABV - alcohol by volume 40%), or 0.5 litre of beer (ABV 5%), or 200 ml glass of red wine (ABV 12%) or history of alcohol abuse, narcomania, or other drug abuse. A positive urine drug test (cannabis, benzodiazepines, barbiturates, opiates, cocaine, amphetamines) at screening and before the first dosing in each study period. A positive alcohol test at screening and before the first dosing in each study period Participation in another phase I clinical study within 3 months before inclusion into the study. Known lactose intolerance. Known phenylketonuria

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment sequence 1<br>Treatment 1, Washout 6 days, Reference product, Washout 6 days, Treatment 2 | Drug: Lasolvan tablet<br>* One Lasolvan tablet 30 mg twice daily for 5 days.<br>Drug: Lasolvan prolonged-released capsules<br>* One Lasolvan prolonged-release hard capsule 75 mg once daily for 5 days<br>Drug: Lasolvan effervescent tablet<br>* One-half Lasolvan effervescent tablet 60mg twice daily for 5 days.<br>|
| Experimental: Treatment sequence 2<br>Treatment 2, Washout period 6 days, Treatment 1, Washout 6 days, Reference product | Drug: Lasolvan tablet<br>* One Lasolvan tablet 30 mg twice daily for 5 days.<br>Drug: Lasolvan effervescent tablet<br>* One-half Lasolvan effervescent tablet 60mg twice daily for 5 days.<br>Drug: Lasolvan prolonged-release hard capsule<br>* One Lasolvan prolonged-release hard capsule 75 mg once daily for 5 days<br>|
| Experimental: Treatment sequence 3<br>Reference product, Washout 6 days, Treatment 2, Washout 6 days, Treatment 1 | Drug: Lasolvan effervescent tablet<br>* One-half Lasolvan effervescent tablet 60mg twice daily for 5 days.<br>Drug: Lasolvan tablet<br>* One Lasolvan tablet 30 mg twice daily for 5 days.<br>Drug: Lasolvan prolonged-release hard capsule<br>* One Lasolvan prolonged-release hard capsule 75 mg once daily for 5 days<br>|
| Experimental: Treatment Sequence 4<br>Treatment 2, Washout 6 days, Reference product, Washout 6 days, Treatment 1 | Drug: Lasolvan tablet<br>* One Lasolvan tablet 30 mg twice daily for 5 days.<br>Drug: Lasolvan effervescent tablet<br>* One-half Lasolvan effervescent tablet 60mg twice daily for 5 days.<br>Drug: Lasolvan prolonged-release hard capsule<br>* One Lasolvan prolonged-release hard capsule 75 mg once daily for 5 days<br>|
| Experimental: Treatment sequence 5<br>Reference product, Washout 6 days, Treatment 1, Washout 6 days, Treatment 2 | Drug: Lasolvan tablet<br>* One Lasolvan tablet 30 mg twice daily for 5 days.<br>Drug: Lasolvan prolonged-release hard capsule<br>* One Lasolvan prolonged-release hard capsule 75 mg once daily for 5 days<br>Drug: Lasolvan effervescent tablet<br>* One-half Lasolvan effervescent tablet 60mg twice daily for 5 days.<br>|
| Experimental: Treatment Sequence 6<br>Treatment 1, Washout 6 days, Treatment 2, Washout 6 days, Reference product | Drug: Lasolvan tablet<br>* One Lasolvan tablet 30 mg twice daily for 5 days.<br>Drug: Lasolvan effervescent tablet<br>* One-half Lasolvan effervescent tablet 60mg twice daily for 5 days.<br>Drug: Lasolvan prolonged-release hard capsule<br>* One Lasolvan prolonged-release hard capsule 75 mg once daily for 5 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to 24 h at Steady State | Area under the concentration-time curve of the analyte in plasma over the time interval from 0 to 24 h at steady state (AUCss 0-24) | Pre-dose, 30min, 1h, 1h 30min, 2h, 3h, 4h, 5h, 6h, 7h 30min, 9h, 10h 30min, 12h, 14h, 17h, 20h, 24h after the morning dose for all treatments; also 15min, 45min, 12h 15min, 12h 30min, 12h 45min, 13h, 13h 30min, 15h, 16h for Lasolvan 60mg and Lasolvan 30mg | 
| Maximum Measured Concentration of the Analyte in Plasma at Steady State | Maximum measured concentration of the analyte in plasma at steady state (Cmax ss) | Pre-dose, 30min, 1h, 1h 30min, 2h, 3h, 4h, 5h, 6h, 7h 30min, 9h, 10h 30min, 12h, 14h, 17h, 20h, 24h after the morning dose for all treatments; also 15min, 45min, 12h 15min, 12h 30min, 12h 45min, 13h, 13h 30min, 15h, 16h for Lasolvan 60mg and Lasolvan 30mg | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Concentration-time Curve of the Analyte in Plasma at Steady State During 0-24 h, Adjusted to a Daily Dose of 60 mg | Area under the concentration-time curve of the analyte in plasma at steady state during 0-24 h, adjusted to a daily dose of 60 mg (AUCss 0-24 norm) | Pre-dose, 30min, 1h, 1h 30min, 2h, 3h, 4h, 5h, 6h, 7h 30min, 9h, 10h 30min, 12h, 14h, 17h, 20h, 24h after the morning dose for all treatments; also 15min, 45min, 12h 15min, 12h 30min, 12h 45min, 13h, 13h 30min, 15h, 16h for Lasolvan 60mg and Lasolvan 30mg | 
| Rate of Absorption at Steady State (Cmax ss/AUCss 0-24) | Metric which characterises the rate of absorption at steady state (Cmax ss/AUCss 0-24) | Pre-dose, 30min, 1h, 1h 30min, 2h, 3h, 4h, 5h, 6h, 7h 30min, 9h, 10h 30min, 12h, 14h, 17h, 20h, 24h after the morning dose for all treatments; also 15min, 45min, 12h 15min, 12h 30min, 12h 45min, 13h, 13h 30min, 15h, 16h for Lasolvan 60mg and Lasolvan 30mg | 
| Steady State Concentration of the Analyte in Plasma at the End of Dosing Interval | Steady state concentration of the analyte in plasma at the end of dosing interval (Cmin ss) | Pre-dose, 30min, 1h, 1h 30min, 2h, 3h, 4h, 5h, 6h, 7h 30min, 9h, 10h 30min, 12h, 14h, 17h, 20h, 24h after the morning dose for all treatments; also 15min, 45min, 12h 15min, 12h 30min, 12h 45min, 13h, 13h 30min, 15h, 16h for Lasolvan 60mg and Lasolvan 30mg | 
| Average Concentration of the Analyte in Plasma in the Time Interval of 0 to 24 h at Steady State | Average concentration of the analyte in plasma in the time interval of 0 to 24 h at steady state (Cav ss) | Pre-dose, 30min, 1h, 1h 30min, 2h, 3h, 4h, 5h, 6h, 7h 30min, 9h, 10h 30min, 12h, 14h, 17h, 20h, 24h after the morning dose for all treatments; also 15min, 45min, 12h 15min, 12h 30min, 12h 45min, 13h, 13h 30min, 15h, 16h for Lasolvan 60mg and Lasolvan 30mg | 
| Time From Dosing to the Maximum Concentration of the Analyte in Plasma at Steady State | Time from dosing to the maximum concentration of the analyte in plasma at steady state (tmax ss). For Lasolvan 30mg and Lasolvan 60mg, tmax ss was determined as tmax ss 0-12 and tmax ss 12-24. | Pre-dose, 30min, 1h, 1h 30min, 2h, 3h, 4h, 5h, 6h, 7h 30min, 9h, 10h 30min, 12h, 14h, 17h, 20h, 24h after the morning dose for all treatments; also 15min, 45min, 12h 15min, 12h 30min, 12h 45min, 13h, 13h 30min, 15h, 16h for Lasolvan 60mg and Lasolvan 30mg | 
| Peak-trough Fluctuation Between Minimum and Maximum Concentration of the Analyte in Plasma | Peak-trough fluctuation between minimum and maximum concentration of the analyte in plasma (PTF) | Pre-dose, 30min, 1h, 1h 30min, 2h, 3h, 4h, 5h, 6h, 7h 30min, 9h, 10h 30min, 12h, 14h, 17h, 20h, 24h after the morning dose for all treatments; also 15min, 45min, 12h 15min, 12h 30min, 12h 45min, 13h, 13h 30min, 15h, 16h for Lasolvan 60mg and Lasolvan 30mg | 
| Peak-trough Swing | Peak-trough swing (PTS) calculated as ((Cmax,ss - Cmin,ss / Cav,ss)*100) | Pre-dose, 30min, 1h, 1h 30min, 2h, 3h, 4h, 5h, 6h, 7h 30min, 9h, 10h 30min, 12h, 14h, 17h, 20h, 24h after the morning dose for all treatments; also 15min, 45min, 12h 15min, 12h 30min, 12h 45min, 13h, 13h 30min, 15h, 16h for Lasolvan 60mg and Lasolvan 30mg | 
| Time Period When Concentration of the Analyte Exceeds Cav ss | Time period when the concentration of the analyte exceeds Cav ss (T (C>Cav ss)) | Pre-dose, 30min, 1h, 1h 30min, 2h, 3h, 4h, 5h, 6h, 7h 30min, 9h, 10h 30min, 12h, 14h, 17h, 20h, 24h after the morning dose for all treatments; also 15min, 45min, 12h 15min, 12h 30min, 12h 45min, 13h, 13h 30min, 15h, 16h for Lasolvan 60mg and Lasolvan 30mg | 
| Plateau Time During Which Concentration of the Analyte in Plasma Exceeds 75% of Cmax ss | Plateau time during which concentration of the analyte in plasma exceeds 75% of Cmax ss (T(C>75% Cmax ss)) | Pre-dose, 30min, 1h, 1h 30min, 2h, 3h, 4h, 5h, 6h, 7h 30min, 9h, 10h 30min, 12h, 14h, 17h, 20h, 24h after the morning dose for all treatments; also 15min, 45min, 12h 15min, 12h 30min, 12h 45min, 13h, 13h 30min, 15h, 16h for Lasolvan 60mg and Lasolvan 30mg |