Healthy Lactating Women
Conditions
Keywords
pharmacokinetic, pregabalin, lactation
Brief summary
This is a pharmacokinetic study to determine the safety and tolerability of pregabalin in healthy lactating women. The objectives are to determine whether pregabalin is secreted in breast milk and if so, to characterize pregabalin pharmacokinetics in breast milk. Other objectives are to estimate potential infant exposure to pregabalin if administered to lactating women and to characterize the safety and tolerability of pregabalin in lactating women.
Detailed description
Post approval commitment for the FDA
Interventions
Subjects will receive a single 150 mg dose of pregabalin in the evening of Day 1, a 150 mg dose of pregabalin in the morning and evening of Day 2 and a 150 mg dose in the morning of Day 3.
Sponsors
Pfizer's Upjohn has merged with Mylan to form Viatris Inc.
Study design
Allocation
NON_RANDOMIZED
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy lactating females between the ages of 18 and 45 years (inclusive) who are actively breast-feeding or expressing breast milk and are at least 12 weeks post partum. * Subjects must be willing to temporarily discontinue breast feeding their infants before the Day 1 evening dose through to 42 hours after the last dose
Exclusion criteria
* History of significant adverse reaction to pregabalin or gabapentin. * Subjects pregnant or unwilling or unable to comply with the Lifestyle guidelines presented in the protocol during the study period and through the follow-up visit. * Subjects with evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric (including post natal depression), neurologic or allergic disease (including drug allergies, but excluding untreated asymptomatic, seasonal allergies at time of dosing).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Infant Dose Expressed as Percentage of Body Weight Normalized Maternal Dose (BWNIDPCM) | Pre-dose to 24 hours post-dose on Day 3 | Infant dose expressed as percentage of body weight normalized maternal dose (BWNIDPCM) was the relative infant dose (relative to maternal dose) calculated by the formula: 100 \* BWNID (Body Weight Normalized Infant Dose) / Body Weight Normalized Maternal Dose (BWNMD), where tau was the dosing interval of 12 hours. |
| Milk to Plasma Ratio for Maximum Observed Concentration (MPCmax) | Plasma: Pre-dose on Day 3; 0.5, 1, 2, 3, 4, 6, 10, 12, 18, 24 hours post-dose on Day 3. Breast milk: Pre-dose on Day 3; 0 to 2, 2 to 4, 4 to 8, 8 to 12, 12 to 24, 24 to 32, 32 to 40 and 40 to 48 hours post-dose on Day 3 | Milk to plasma ratio for maximum observed concentration (MPCmax) was calculated as the ratio of Cmax (breast milk) to Cmax (plasma). |
| Body Weight Normalized Infant Dose (BWNID) | Plasma: Pre-dose on Day 3; 0.5, 1, 2, 3, 4, 6, 10, 12 hours post-dose on Day 3. Breast milk: Pre-dose on Day 3; 0 to 2, 2 to 4, 4 to 8, 8 to 12 hours post-dose on Day 3 | Body weight normalized infant dose (BWNID) of pregabalin was the dose that an infant received from breast-feeding and was calculated from the milk to plasma AUCtau ratio multiplied by the average maternal plasma pregabalin concentration (Cav) multiplied by the standardized milk consumption for an infant (150 milliliter/kilogram/day \[mL/kg/day\]), where tau was the dosing interval of 12 hours. |
| Body Weight Normalized Maternal Dose (BWNMD) | Pre-dose to 24 hours post-dose on Day 3 | Body weight normalized maternal dose (BWNMD) was calculated as the maternal dose in microgram per day (mcg/day) divided by maternal weight in kilogram (kg) at screening. |
| Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) | Pre-dose on Day 3; 0.5, 1, 2, 3, 4, 6, 10, 12 hours post-dose on Day 3 | Area under the plasma concentration-time profile from time 0 to tau (AUCtau), where tau was the dosing interval of 12 hours. |
| Maximum Observed Plasma Concentration (Cmax) | Pre-dose on Day 3; 0.5, 1, 2, 3, 4, 6, 10, 12, 18, 24 hours post-dose on Day 3 | Cmax was the peak concentration in plasma post Day 3 dose. |
| Time to Reach Maximum Observed Plasma Concentration (Tmax) | Pre-dose on Day 3; 0.5, 1, 2, 3, 4, 6, 10, 12, 18, 24 hours post-dose on Day 3 | Tmax was the time to peak concentration in plasma post Day 3 dose. |
| Plasma Half-Life (t1/2) | Pre-dose on Day 3; 0.5, 1, 2, 3, 4, 6, 10, 12, 18, 24 hours post-dose on Day 3 | Plasma decay half-life (t1/2) was the time for the plasma concentration to decrease by one-half. The t1/2 is based on the terminal elimination phase time points from this timeframe. |
| Average Plasma Concentration During the Dosing Interval (Cav) | Pre-dose on Day 3; 0.5, 1, 2, 3, 4, 6, 10, 12 hours post-dose on Day 3 | Average plasma concentration during the dosing interval (Cav) was calculated by dividing AUCtau (plasma) with tau, where tau was the dosing interval of 12 hours. |
| Minimum Observed Plasma Trough Concentration (Cmin) | Pre-dose on Day 3; 0.5, 1, 2, 3, 4, 6, 10, 12, 18, 24 hours post-dose on Day 3 | Cmin was the minimum observed plasma concentration of a drug after post Day 3 dose. |
| Apparent Oral Clearance (CL/F) | Pre-dose on Day 3; 0.5, 1, 2, 3, 4, 6, 10, 12 hours post-dose on Day 3 | Apparent oral clearance (CL/F) was calculated by dividing dose by the AUCtau, where tau was the dosing interval of 12 hours. Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. |
| Area Under the Curve From Time Zero to End of Dosing Interval for Breast Milk (AUCtau [Breast Milk]) | Pre-dose on Day 3; 0 to 2, 2 to 4, 4 to 8, 8 to 12 hours post-dose on Day 3 | AUCtau (breast milk) was the area under the curve for breast milk, from time 0 to tau (AUCtau), where tau was the dosing interval of 12 hours. |
| Maximum Observed Concentration in Breast Milk (Cmax [Breast Milk]) | Pre-dose on Day 3; 0 to 2, 2 to 4, 4 to 8, 8 to 12, 12 to 24, 24 to 32, 32 to 40 and 40 to 48 hours post-dose on Day 3 | Cmax (breast milk) was the maximum observed concentration in breast milk post Day 3 dose. |
| Time to Reach Maximum Observed Breast Milk Concentration (Tmax [Breast Milk]) | Pre-dose on Day 3; 0 to 2, 2 to 4, 4 to 8, 8 to 12, 12 to 24, 24 to 32, 32 to 40 and 40 to 48 hours post-dose on Day 3 | Tmax (breast milk) was time of the maximum observed breast milk concentration Day 3 post-dose. |
| Terminal Half-Life for Breast Milk (t1/2 [Breast Milk]) | Pre-dose on Day 3; 0 to 2, 2 to 4, 4 to 8, 8 to 12, 12 to 24, 24 to 32, 32 to 40 and 40 to 48 hours post-dose on Day 3 | The terminal half-life for breast milk (t1/2 \[breast milk\]) was the time measured for breast milk concentration to decrease by one-half. For the first 5 participants enrolled under protocol amendment dated: 18 Sep 2012, breast milk was collected up to 24 hours after Day 3 dosing over the following time intervals: 0 to 2, 2 to 4, 4 to 8, 8 to 12, 12 to 24 hours. Terminal half-life was determined over those points characterizing the elimination phase. For the remaining 5 participants, there were 3 additional collection intervals (24 to 32, 32 to 40, 40 to 48 hours) for characterizing the terminal elimination phase. The t1/2 (breast milk) is based on the terminal elimination phase time points from this timeframe. |
| Average Breast Milk Concentration During the Dosing Interval (Cav) | Pre-dose on Day 3; 0 to 2, 2 to 4, 4 to 8, 8 to 12 hours post-dose on Day 3 | Average breast milk concentration during the dosing interval (Cav) was calculated by dividing AUCtau (breast milk) with tau, where tau was the dosing interval of 12 hours. |
| Amount Excreted in Breast Milk Over the Dosing Interval Tau (Aetaubm) | Pre-dose on Day 3; 0 to 2, 2 to 4, 4 to 8, 8 to 12 hours post-dose on Day 3 | Aetaubm was the amount excreted in breast milk over the dosing interval tau (12 hours). It was calculated as the sum of (breast milk concentration \* sample volume) for each collection interval from 0 to 12 hours post-dose, where tau was the dosing interval of 12 hours. Sample volume was based on ratio of volume weight and density. |
| Percentage of Dose Excreted in Breast Milk During the Dosing Interval Tau (Aetaubm Percent) | Pre-dose on Day 3; 0 to 2, 2 to 4, 4 to 8, 8 to 12 hours post-dose on Day 3 | Percentage of dose excreted in breast milk during the dosing interval tau (Aetaubm percent) was calculated by using the formula: 100\*(Aetaubm \[sum of {breast milk concentration \* sample volume} for each collection interval from 0 to 12 hours post-dose\] divided by dose), where tau was the dosing interval of 12 hours. |
| Breast Milk Clearance (CLbm) | Plasma: Pre-dose on Day 3; 0.5, 1, 2, 3, 4, 6, 10, 12 hours post-dose on Day 3. Breast milk: Pre-dose on Day 3; 0 to 2, 2 to 4, 4 to 8, 8 to 12 hours post-dose on Day 3 | Breast milk clearance (CLbm) was calculated by dividing Aetaubm (sum of \[breast milk concentration \* sample volume\] for each collection interval from 0 to 12 hours post-dose) by plasma AUCtau, where tau was the dosing interval of 12 hours. |
| Amount Recovered in Urine During the Dosing Interval Tau (Aetauurine) | Pre-dose on Day 3; 0 to 2, 2 to 4, 4 to 8, 8 to 12 hours post-dose on Day 3 | Aetauurine was the amount excreted in urine over the dosing interval tau (12 hours). It was calculated as the sum of (urine concentration \* sample volume) for each collection interval from 0 to 12 hours post-dose, where tau was the dosing interval of 12 hours. Here, sample volume was based on the ratio of volume weight and density. |
| Percent of Dose Recovered in Urine During the Dosing Interval Tau (Aetauurine Percent) | Pre-dose on Day 3; 0 to 2, 2 to 4, 4 to 8, 8 to 12 hours post-dose on Day 3 | Percent of dose recovered in urine during the dosing interval tau (Aetauurine percent) was calculated as 100\* (Aetau \[sum of {urine concentration \* sample volume} for each collection interval from 0 to 12 hours post-dose\] divided by the dose), where tau was the dosing interval of 12 hours. |
| Renal Clearance (CLr) | Plasma: Pre-dose on Day 3; 0.5, 1, 2, 3, 4, 6, 10, 12 hours post-dose on Day 3. Urine: Pre-dose on Day 3; 0 to 2, 2 to 4, 4 to 8 and 8 to 12 hours post-dose on Day 3 | Renal clearance (CLr) was the volume of plasma from which the drug was completely removed by the kidney in a given amount of time. It was calculated by dividing Aetauurine (sum of \[urine concentration \* sample volume\] for each collection interval from 0 to 12 hours post-dose) with the plasma AUCtau, where tau was the dosing interval of 12 hours. |
| Daily Amount of Pregabalin Excreted in Breast Milk (Ae24bm) | Pre-dose on Day 3; 0 to 2, 2 to 4, 4 to 8, 8 to 12 hours post-dose on Day 3 | Ae24bm was the daily amount of pregabalin excreted in breast milk. It was calculated by the formula: 2 \* Aetaubm (sum of \[breast milk concentration \* sample volume\] for each collection interval from 0 to 12 hours post-dose), where tau was the dosing interval of 12 hours. |
| Milk to Plasma Ratio for AUCtau (MPAUCtau) | Plasma: Pre-dose on Day 3; 0.5, 1, 2, 3, 4, 6, 10, 12 hours post-dose on Day 3. Breast milk: Pre-dose on Day 3; 0 to 2, 2 to 4, 4 to 8, 8 to 12 hours post-dose on Day 3 | MPAUCtau was the ratio of AUCtau (breast milk) to AUCtau (plasma), where tau was the dosing interval of 12 hours. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Laboratory Abnormalities | Baseline up to 28 days after last dose of study drug | The following parameters were analyzed for laboratory abnormalities: hematology (hemoglobin, hematocrit, red blood cell count, mean corpuscular volume \[MCV\], mean corpuscular hemoglobin \[MCH\], mean corpuscular hemoglobin concentration \[MCHC\], platelets, white blood cell count, lymphocytes, total neutrophils, basophils, eosinophils, monocytes); liver function (bilirubin, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, total protein, albumin); renal function (blood urea nitrogen, creatinine, uric acid); electrolytes (sodium, potassium, chloride, calcium, bicarbonate); clinical chemistry (glucose); urinalysis (urine pH, glucose, ketones, protein, urine blood/hemoglobin, nitrite). |
| Number of Participants With Clinically Significant Change From Baseline in Vital Signs | Baseline up to 28 days after last dose of study drug | The following parameters were analyzed for examination of vital signs: electrocardiogram (ECG), systolic and diastolic blood pressure, temperature, pulse rate, respiratory rate, radial pulse and body temperature. |
| Number of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) | Baseline up to 28 days after last dose of study drug | An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pretreatment state. AEs included both SAEs and non-SAEs. |
Countries
Belgium
Participant flow
Recruitment details
Eligible participants were healthy, lactating females between the ages of 18 and 45 years (inclusive) who were actively breastfeeding or expressing breast milk, who were at least 12 weeks post-partum and not currently pregnant.
Participants by arm
| Arm | Count |
|---|---|
| Pregabalin Participants received pregabalin 150 milligram (mg) immediate-release (IR) capsule over 12-hour dosing intervals on Day 1, Day 2 and Day 3. | 10 |
| Total | 10 |
Baseline characteristics
| Characteristic | Pregabalin |
|---|---|
| Age, Continuous | 31.7 years STANDARD_DEVIATION 4.5 |
| Sex: Female, Male Female | 10 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 8 / 10 |
| serious Total, serious adverse events | 0 / 10 |
Outcome results
Primary
Amount Excreted in Breast Milk Over the Dosing Interval Tau (Aetaubm)
Aetaubm was the amount excreted in breast milk over the dosing interval tau (12 hours). It was calculated as the sum of (breast milk concentration \* sample volume) for each collection interval from 0 to 12 hours post-dose, where tau was the dosing interval of 12 hours. Sample volume was based on ratio of volume weight and density.
Time frame: Pre-dose on Day 3; 0 to 2, 2 to 4, 4 to 8, 8 to 12 hours post-dose on Day 3
Population: The PK parameter analysis population included participants who received study medication and who had at least 1 of the PK parameters of primary interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Pregabalin | Amount Excreted in Breast Milk Over the Dosing Interval Tau (Aetaubm) | 286.9 mcg | Geometric Coefficient of Variation 60 |
Primary
Amount Recovered in Urine During the Dosing Interval Tau (Aetauurine)
Aetauurine was the amount excreted in urine over the dosing interval tau (12 hours). It was calculated as the sum of (urine concentration \* sample volume) for each collection interval from 0 to 12 hours post-dose, where tau was the dosing interval of 12 hours. Here, sample volume was based on the ratio of volume weight and density.
Time frame: Pre-dose on Day 3; 0 to 2, 2 to 4, 4 to 8, 8 to 12 hours post-dose on Day 3
Population: The PK parameter analysis population included participants who received study medication and who had at least 1 of the PK parameters of primary interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Pregabalin | Amount Recovered in Urine During the Dosing Interval Tau (Aetauurine) | 133.1 mg | Geometric Coefficient of Variation 12 |
Primary
Apparent Oral Clearance (CL/F)
Apparent oral clearance (CL/F) was calculated by dividing dose by the AUCtau, where tau was the dosing interval of 12 hours. Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.
Time frame: Pre-dose on Day 3; 0.5, 1, 2, 3, 4, 6, 10, 12 hours post-dose on Day 3
Population: The PK parameter analysis population included participants who received study medication and who had at least 1 of the PK parameters of primary interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Pregabalin | Apparent Oral Clearance (CL/F) | 76.90 mL/minute | Geometric Coefficient of Variation 24 |
Primary
Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau)
Area under the plasma concentration-time profile from time 0 to tau (AUCtau), where tau was the dosing interval of 12 hours.
Time frame: Pre-dose on Day 3; 0.5, 1, 2, 3, 4, 6, 10, 12 hours post-dose on Day 3
Population: The pharmacokinetic (PK) parameter analysis population included participants who received study medication and who had at least 1 of the PK parameters of primary interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Pregabalin | Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) | 32.50 microgram*hour/milliliter (mcg*hr/mL) | Geometric Coefficient of Variation 24 |
Primary
Area Under the Curve From Time Zero to End of Dosing Interval for Breast Milk (AUCtau [Breast Milk])
AUCtau (breast milk) was the area under the curve for breast milk, from time 0 to tau (AUCtau), where tau was the dosing interval of 12 hours.
Time frame: Pre-dose on Day 3; 0 to 2, 2 to 4, 4 to 8, 8 to 12 hours post-dose on Day 3
Population: The PK parameter analysis population included participants who received study medication and who had at least 1 of the PK parameters of primary interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Pregabalin | Area Under the Curve From Time Zero to End of Dosing Interval for Breast Milk (AUCtau [Breast Milk]) | 24.64 mcg*hr/mL | Geometric Coefficient of Variation 27 |
Primary
Average Breast Milk Concentration During the Dosing Interval (Cav)
Average breast milk concentration during the dosing interval (Cav) was calculated by dividing AUCtau (breast milk) with tau, where tau was the dosing interval of 12 hours.
Time frame: Pre-dose on Day 3; 0 to 2, 2 to 4, 4 to 8, 8 to 12 hours post-dose on Day 3
Population: The PK parameter analysis population included participants who received study medication and who had at least 1 of the PK parameters of primary interest.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pregabalin | Average Breast Milk Concentration During the Dosing Interval (Cav) | 2.116 mcg/mL | Full Range 27 |
Primary
Average Plasma Concentration During the Dosing Interval (Cav)
Average plasma concentration during the dosing interval (Cav) was calculated by dividing AUCtau (plasma) with tau, where tau was the dosing interval of 12 hours.
Time frame: Pre-dose on Day 3; 0.5, 1, 2, 3, 4, 6, 10, 12 hours post-dose on Day 3
Population: The PK parameter analysis population included participants who received study medication and who had at least 1 of the PK parameters of primary interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Pregabalin | Average Plasma Concentration During the Dosing Interval (Cav) | 2.709 mcg/mL | Geometric Coefficient of Variation 24 |
Primary
Body Weight Normalized Infant Dose (BWNID)
Body weight normalized infant dose (BWNID) of pregabalin was the dose that an infant received from breast-feeding and was calculated from the milk to plasma AUCtau ratio multiplied by the average maternal plasma pregabalin concentration (Cav) multiplied by the standardized milk consumption for an infant (150 milliliter/kilogram/day \[mL/kg/day\]), where tau was the dosing interval of 12 hours.
Time frame: Plasma: Pre-dose on Day 3; 0.5, 1, 2, 3, 4, 6, 10, 12 hours post-dose on Day 3. Breast milk: Pre-dose on Day 3; 0 to 2, 2 to 4, 4 to 8, 8 to 12 hours post-dose on Day 3
Population: The PK parameter analysis population included participants who received study medication and who had at least 1 of the PK parameters of primary interest.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pregabalin | Body Weight Normalized Infant Dose (BWNID) | 317.3 mcg/kg/day | Full Range 27 |
Primary
Body Weight Normalized Maternal Dose (BWNMD)
Body weight normalized maternal dose (BWNMD) was calculated as the maternal dose in microgram per day (mcg/day) divided by maternal weight in kilogram (kg) at screening.
Time frame: Pre-dose to 24 hours post-dose on Day 3
Population: The PK parameter analysis population included participants who received study medication and who had at least 1 of the PK parameters of primary interest.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pregabalin | Body Weight Normalized Maternal Dose (BWNMD) | 4343.6 mcg/kg/day | Full Range 27 |
Primary
Breast Milk Clearance (CLbm)
Breast milk clearance (CLbm) was calculated by dividing Aetaubm (sum of \[breast milk concentration \* sample volume\] for each collection interval from 0 to 12 hours post-dose) by plasma AUCtau, where tau was the dosing interval of 12 hours.
Time frame: Plasma: Pre-dose on Day 3; 0.5, 1, 2, 3, 4, 6, 10, 12 hours post-dose on Day 3. Breast milk: Pre-dose on Day 3; 0 to 2, 2 to 4, 4 to 8, 8 to 12 hours post-dose on Day 3
Population: The PK parameter analysis population included participants who received study medication and who had at least 1 of the PK parameters of primary interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Pregabalin | Breast Milk Clearance (CLbm) | 0.1473 mL/min | Geometric Coefficient of Variation 60 |
Primary
Daily Amount of Pregabalin Excreted in Breast Milk (Ae24bm)
Ae24bm was the daily amount of pregabalin excreted in breast milk. It was calculated by the formula: 2 \* Aetaubm (sum of \[breast milk concentration \* sample volume\] for each collection interval from 0 to 12 hours post-dose), where tau was the dosing interval of 12 hours.
Time frame: Pre-dose on Day 3; 0 to 2, 2 to 4, 4 to 8, 8 to 12 hours post-dose on Day 3
Population: The PK parameter analysis population included participants who received study medication and who had at least 1 of the PK parameters of primary interest.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pregabalin | Daily Amount of Pregabalin Excreted in Breast Milk (Ae24bm) | 664.6 mcg | Full Range 60 |
Primary
Infant Dose Expressed as Percentage of Body Weight Normalized Maternal Dose (BWNIDPCM)
Infant dose expressed as percentage of body weight normalized maternal dose (BWNIDPCM) was the relative infant dose (relative to maternal dose) calculated by the formula: 100 \* BWNID (Body Weight Normalized Infant Dose) / Body Weight Normalized Maternal Dose (BWNMD), where tau was the dosing interval of 12 hours.
Time frame: Pre-dose to 24 hours post-dose on Day 3
Population: The PK parameter analysis population included participants who received study medication and who had at least 1 of the PK parameters of primary interest.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pregabalin | Infant Dose Expressed as Percentage of Body Weight Normalized Maternal Dose (BWNIDPCM) | 7.341 percentage of dose | Full Range 27 |
Primary
Maximum Observed Concentration in Breast Milk (Cmax [Breast Milk])
Cmax (breast milk) was the maximum observed concentration in breast milk post Day 3 dose.
Time frame: Pre-dose on Day 3; 0 to 2, 2 to 4, 4 to 8, 8 to 12, 12 to 24, 24 to 32, 32 to 40 and 40 to 48 hours post-dose on Day 3
Population: The PK parameter analysis population included participants who received study medication and who had at least 1 of the PK parameters of primary interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Pregabalin | Maximum Observed Concentration in Breast Milk (Cmax [Breast Milk]) | 2.474 mcg/mL | Geometric Coefficient of Variation 30 |
Primary
Maximum Observed Plasma Concentration (Cmax)
Cmax was the peak concentration in plasma post Day 3 dose.
Time frame: Pre-dose on Day 3; 0.5, 1, 2, 3, 4, 6, 10, 12, 18, 24 hours post-dose on Day 3
Population: The PK parameter analysis population included participants who received study medication and who had at least 1 of the PK parameters of primary interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Pregabalin | Maximum Observed Plasma Concentration (Cmax) | 4.67 mcg/mL | Geometric Coefficient of Variation 18 |
Primary
Milk to Plasma Ratio for AUCtau (MPAUCtau)
MPAUCtau was the ratio of AUCtau (breast milk) to AUCtau (plasma), where tau was the dosing interval of 12 hours.
Time frame: Plasma: Pre-dose on Day 3; 0.5, 1, 2, 3, 4, 6, 10, 12 hours post-dose on Day 3. Breast milk: Pre-dose on Day 3; 0 to 2, 2 to 4, 4 to 8, 8 to 12 hours post-dose on Day 3
Population: The PK parameter analysis population included participants who received study medication and who had at least 1 of the PK parameters of primary interest.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Pregabalin | Milk to Plasma Ratio for AUCtau (MPAUCtau) | 0.769 ratio |
Primary
Milk to Plasma Ratio for Maximum Observed Concentration (MPCmax)
Milk to plasma ratio for maximum observed concentration (MPCmax) was calculated as the ratio of Cmax (breast milk) to Cmax (plasma).
Time frame: Plasma: Pre-dose on Day 3; 0.5, 1, 2, 3, 4, 6, 10, 12, 18, 24 hours post-dose on Day 3. Breast milk: Pre-dose on Day 3; 0 to 2, 2 to 4, 4 to 8, 8 to 12, 12 to 24, 24 to 32, 32 to 40 and 40 to 48 hours post-dose on Day 3
Population: The PK parameter analysis population included participants who received study medication and who had at least 1 of the PK parameters of primary interest.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Pregabalin | Milk to Plasma Ratio for Maximum Observed Concentration (MPCmax) | 0.5413 ratio |
Primary
Minimum Observed Plasma Trough Concentration (Cmin)
Cmin was the minimum observed plasma concentration of a drug after post Day 3 dose.
Time frame: Pre-dose on Day 3; 0.5, 1, 2, 3, 4, 6, 10, 12, 18, 24 hours post-dose on Day 3
Population: The PK parameter analysis population included participants who received study medication and who had at least 1 of the PK parameters of primary interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Pregabalin | Minimum Observed Plasma Trough Concentration (Cmin) | 1.246 mcg/mL | Geometric Coefficient of Variation 36 |
Primary
Percentage of Dose Excreted in Breast Milk During the Dosing Interval Tau (Aetaubm Percent)
Percentage of dose excreted in breast milk during the dosing interval tau (Aetaubm percent) was calculated by using the formula: 100\*(Aetaubm \[sum of {breast milk concentration \* sample volume} for each collection interval from 0 to 12 hours post-dose\] divided by dose), where tau was the dosing interval of 12 hours.
Time frame: Pre-dose on Day 3; 0 to 2, 2 to 4, 4 to 8, 8 to 12 hours post-dose on Day 3
Population: The PK parameter analysis population included participants who received study medication and who had at least 1 of the PK parameters of primary interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Pregabalin | Percentage of Dose Excreted in Breast Milk During the Dosing Interval Tau (Aetaubm Percent) | 0.1913 percentage of dose | Geometric Coefficient of Variation 60 |
Primary
Percent of Dose Recovered in Urine During the Dosing Interval Tau (Aetauurine Percent)
Percent of dose recovered in urine during the dosing interval tau (Aetauurine percent) was calculated as 100\* (Aetau \[sum of {urine concentration \* sample volume} for each collection interval from 0 to 12 hours post-dose\] divided by the dose), where tau was the dosing interval of 12 hours.
Time frame: Pre-dose on Day 3; 0 to 2, 2 to 4, 4 to 8, 8 to 12 hours post-dose on Day 3
Population: The PK parameter analysis population included participants who received study medication and who had at least 1 of the PK parameters of primary interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Pregabalin | Percent of Dose Recovered in Urine During the Dosing Interval Tau (Aetauurine Percent) | 88.6 percentage of dose | Geometric Coefficient of Variation 12 |
Primary
Plasma Half-Life (t1/2)
Plasma decay half-life (t1/2) was the time for the plasma concentration to decrease by one-half. The t1/2 is based on the terminal elimination phase time points from this timeframe.
Time frame: Pre-dose on Day 3; 0.5, 1, 2, 3, 4, 6, 10, 12, 18, 24 hours post-dose on Day 3
Population: The PK parameter analysis population included participants who received study medication and who had at least 1 of the PK parameters of primary interest.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pregabalin | Plasma Half-Life (t1/2) | 5.624 hr | Standard Deviation 0.65656 |
Primary
Renal Clearance (CLr)
Renal clearance (CLr) was the volume of plasma from which the drug was completely removed by the kidney in a given amount of time. It was calculated by dividing Aetauurine (sum of \[urine concentration \* sample volume\] for each collection interval from 0 to 12 hours post-dose) with the plasma AUCtau, where tau was the dosing interval of 12 hours.
Time frame: Plasma: Pre-dose on Day 3; 0.5, 1, 2, 3, 4, 6, 10, 12 hours post-dose on Day 3. Urine: Pre-dose on Day 3; 0 to 2, 2 to 4, 4 to 8 and 8 to 12 hours post-dose on Day 3
Population: The PK parameter analysis population included participants who received study medication and who had at least 1 of the PK parameters of primary interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Pregabalin | Renal Clearance (CLr) | 68.16 mL/min | Geometric Coefficient of Variation 24 |
Primary
Terminal Half-Life for Breast Milk (t1/2 [Breast Milk])
The terminal half-life for breast milk (t1/2 \[breast milk\]) was the time measured for breast milk concentration to decrease by one-half. For the first 5 participants enrolled under protocol amendment dated: 18 Sep 2012, breast milk was collected up to 24 hours after Day 3 dosing over the following time intervals: 0 to 2, 2 to 4, 4 to 8, 8 to 12, 12 to 24 hours. Terminal half-life was determined over those points characterizing the elimination phase. For the remaining 5 participants, there were 3 additional collection intervals (24 to 32, 32 to 40, 40 to 48 hours) for characterizing the terminal elimination phase. The t1/2 (breast milk) is based on the terminal elimination phase time points from this timeframe.
Time frame: Pre-dose on Day 3; 0 to 2, 2 to 4, 4 to 8, 8 to 12, 12 to 24, 24 to 32, 32 to 40 and 40 to 48 hours post-dose on Day 3
Population: The PK parameter analysis population included participants who received study medication and who had at least 1 of the PK parameters of primary interest.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pregabalin | Terminal Half-Life for Breast Milk (t1/2 [Breast Milk]) | 8.117 hr | Standard Deviation 3.0871 |
Primary
Time to Reach Maximum Observed Breast Milk Concentration (Tmax [Breast Milk])
Tmax (breast milk) was time of the maximum observed breast milk concentration Day 3 post-dose.
Time frame: Pre-dose on Day 3; 0 to 2, 2 to 4, 4 to 8, 8 to 12, 12 to 24, 24 to 32, 32 to 40 and 40 to 48 hours post-dose on Day 3
Population: The PK parameter analysis population included participants who received study medication and who had at least 1 of the PK parameters of primary interest.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pregabalin | Time to Reach Maximum Observed Breast Milk Concentration (Tmax [Breast Milk]) | 4.63 hr |
Primary
Time to Reach Maximum Observed Plasma Concentration (Tmax)
Tmax was the time to peak concentration in plasma post Day 3 dose.
Time frame: Pre-dose on Day 3; 0.5, 1, 2, 3, 4, 6, 10, 12, 18, 24 hours post-dose on Day 3
Population: The PK parameter analysis population included participants who received study medication and who had at least 1 of the PK parameters of primary interest.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pregabalin | Time to Reach Maximum Observed Plasma Concentration (Tmax) | 2.01 hr |
Other Pre-specified
Number of Participants With Clinically Significant Change From Baseline in Vital Signs
The following parameters were analyzed for examination of vital signs: electrocardiogram (ECG), systolic and diastolic blood pressure, temperature, pulse rate, respiratory rate, radial pulse and body temperature.
Time frame: Baseline up to 28 days after last dose of study drug
Population: The safety analysis population included participants who received at least 1 dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pregabalin | Number of Participants With Clinically Significant Change From Baseline in Vital Signs | 0 participants |
Other Pre-specified
Number of Participants With Laboratory Abnormalities
The following parameters were analyzed for laboratory abnormalities: hematology (hemoglobin, hematocrit, red blood cell count, mean corpuscular volume \[MCV\], mean corpuscular hemoglobin \[MCH\], mean corpuscular hemoglobin concentration \[MCHC\], platelets, white blood cell count, lymphocytes, total neutrophils, basophils, eosinophils, monocytes); liver function (bilirubin, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, total protein, albumin); renal function (blood urea nitrogen, creatinine, uric acid); electrolytes (sodium, potassium, chloride, calcium, bicarbonate); clinical chemistry (glucose); urinalysis (urine pH, glucose, ketones, protein, urine blood/hemoglobin, nitrite).
Time frame: Baseline up to 28 days after last dose of study drug
Population: The safety analysis population included participants who received at least 1 dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pregabalin | Number of Participants With Laboratory Abnormalities | 4 participants |
Other Pre-specified
Number of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs)
An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pretreatment state. AEs included both SAEs and non-SAEs.
Time frame: Baseline up to 28 days after last dose of study drug
Population: The safety analysis population included participants who received at least 1 dose of study medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pregabalin | Number of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) | Number of Participants with AEs | 8 participants |
| Pregabalin | Number of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) | Number of Participants with SAEs | 0 participants |