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Reduced Blood-brain Barrier Penetration of Sarecycline Relative to Minocycline in Rats 
Corresponds with Lipophilicity and Low Vestibular Side Effects

Linda Stein-Gold1, Angela Moore2,3, S. Ken Tanaka4, Jodi L. Johnson5, Ayman Grada6
1Henry Ford Health System, Detroit, Michigan, 2Baylor University Medical Center, Dallas, Texas, USA, 3Arlington Research Center, Arlington, Texas, USA, 4Paratek Pharmaceuticals, Inc. King of Prussia, Pennsylvania, USA, 5Departments of 

Dermatology and Pathology, Feinberg School of Medicine, Northwestern University, USA, 6R&D and Medical Affairs, Almirall (US), Exton, Pennsylvania, USA
Email: Grada@bu.edu

Financial Support: Financial support provided by Almirall, LLC.

Introduction

Methods

Conclusions

Results - Table 1. Unlike minocycline, sarecycline
was not detectable in the brain in rats 

Results - Table 2. Sarecycline has slightly lower 
lipophilicity than minocycline and doxycycline

Discussion - Table 3. Vestibular adverse events were low in Phase 3 
efficacy and safety studies for sarecycline

Time Mcn-pl Scn-pl Mcn-br Scn-br
(hours) µg/mL µg/mL µg/g µg/g

1 0.333 0.460 0.074 BLQ
3 0.174 0.217 0.139 BLQ
6 0.077 0.049 0.068 BLQ

Pl = plasma, Br = brain, Mcn = minocycline, Scn = sarecycline
Limit of quantitation (LOQ) (plasma) = 0.025 µg/mL, LOQ (brain) = 0.05 

µg/g;  BLQ – Below the limit of quantitation

Compound pH 5.5 pH 7.4

Sarecycline HCl -0.16 + 0.01 -0.26 + 0.01

Doxycycline HCl -0.00 + 0.02 -0.18 + 0.03

Minocycline HCl 0.09 + 0.02 0.12 + 0.02

Octanol/water distribution coefficients of sarecycline HCl, minocycline 
HCl, and doxycycline HCl at 25°C. The numbers after ± represent 
standard deviations obtained from triplicate samples. 

 Sarecycline’s inability to cross the blood-brain barrier compared to minocycline corresponds with sarecycline’s lower lipophilicity and may 
explain the low rate of vestibular adverse events observed in sarecycline’s clinical trials.

Discussion - Table 4. Vestibular adverse events were low in an open-
label long-term safety study for sarecycline

Vestibular effects Sarecycline (n=994) Placebo (n=996)
Dizziness 5 (0.5) 11 (1.1)

Vertigo 0 0

Tinnitus 0 0
 Pooled safety data from 2 identical Phase 3 studies (SC1401, SC1402). 
 12 week double-blind treatment with study visits at 3, 6, 9, and 12 weeks 

Vestibular 
effects

Placebo/
Sarecycline

(n=236)

Sarecycline/
Sarecycline

(n=247)
Total (n=483)

Dizziness 1 (0.4) 1 (0.4) 2 (0.4)
Vertigo 0 0 0
Tinnitus 0 0 0

 Patients from previous 12 week Phase 3 studies received once daily sarecycline for up to 40 
weeks.

 Sarecycline is an FDA-approved narrow-spectrum tetracycline-class oral antibiotic 
specifically designed for the treatment of moderate-to-severe acne vulgaris.

 Doxycycline and minocycline have historically been reported with side effects of 
dizziness, vertigo, or tinnitus. 

 Pooled data from 2 Phase III randomized controlled trials (n=2002) and a 40-week 
open-label extension study (n=483) for sarecycline reported low rates of vestibular 
events (dizziness (<0.5%), vertigo (0%), and tinnitus (0%)).

 We sought to investigate penetration of the blood-brain barrier of sarecycline relative 
to minocycline in a rat model and the relative lipophilicity of sarecycline compared to 
minocycline and doxycycline.

Table 1. Blood-brain barrier penetration: Rats (pre-cannulated, 
jugular vein) were dosed with IV sarecycline or minocycline at a total 
dose of 1.0 mg/kg. Rats were fasted overnight (about 16 hours) prior to 
dosing and access to food was restored 2 hours after dosing. Animals 
were euthanized via CO2 and whole blood (via heart puncture) and 
brain were collected from 2 rats at each of the following time points: 1, 3 
and 6 hr post dosing.

Table 2. Lipophilicity: The octanol/water distribution coefficients (logD) 
of sarecycline, minocycline, and doxycycline were measured using the 
shake flask method at pH 5.5 and 7.4 at 25°C. 

Reference: Moore A, Green LJ, Bruce S, et al. Once-Daily Oral Sarecycline 1.5 mg/kg/day Is Effective for Moderate to Severe Acne 
Vulgaris: Results from Two Identically Designed, Phase 3, Randomized, Double-Blind Clinical Trials. Journal of drugs in dermatology: 
JDD. 2018 Sep;17(9):987-96.

Reference: Pariser DM, Green LJ, Lain EL, et al. Safety and Tolerability of Sarecycline for the Treatment of Acne Vulgaris: Results 
from a Phase III, Multicenter, Open-Label Study and a Phase I Phototoxicity Study. Journal of Clinical and Aesthetic Dermatology. 
2019;12(11):E53-E62.

mailto:Grada@bu.edu

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