Population Pharmacokinetic and Pharmacodynamic Analysis of Buprenorphine for the Treatment of Neonatal Abstinence Syndrome
Jason N. Moore, PharmD; Marc Gastonguay; Susan C. Adeniyi-Jones, MD; David E. Moody; and Walter K. Kraft, MD, FACP
Neonatal abstinence syndrome (NAS) is a condition affecting newborns exposed to an opioid in utero. Symptoms of NAS include excessive crying, poor feeding, and disordered autonomic control. Up to 2/3 of infants will require pharmacologic therapies to reach symptom control. Opioids including morphine and methadone are the current first-line treatments. Buprenorphine is being investigated as a treatment of NAS. The purpose of this analysis was to evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of BUP in infants with NAS.
Elizabeth Marek, PharmD; Susan C. Adeniyi-Jones, MD; Lindsey Roke, PharmD; Tara E. DeCerbo, PharmD; Rebecca L. Cordell, PharmD; Paul S. Monks, PharmD; and Walter K. Kraft, MD
Ethanol serves as a solvent and microbial preservative in oral liquid medications and is the second most commonly used solvent in liquid medications following water. Despite widespread use of ethanol in liquid medications for neonates, the pharmacokinetics and toxicity of ethanol in young children are not well described. The aim of the current study is to quantify blood ethanol levels in neonates secondary to oral ethanol containing medications.
Neonates who received either oral phenobarbital (15% ethanol) and/or oral dexamethasone (30% ethanol) per standard of care were eligible for enrollment. A maximum of 6 blood samples per patient (4.5 mL total) were taken over the study period. Blood samples were collected via heel stick at the time of clinical laboratory collections or following a specific collection for study purposes. In addition, blood samples were collected from neonates receiving sublingual buprenorphine (30% ethanol) for neonatal abstinence syndrome from a separate clinical study. Blood ethanol levels were measured using a validated headspace gas chromatography-mass spectrometry method utilizing micro-volume ( ̴100uL) plasma samples. The limit of detection and lower limit of quantification for the assay were 0.1 mg/L and 0.5 mg/L respectively.
A total of 39 plasma samples from 15 neonates who were on ethanol containing medications were collected over the study period. Four neonates were exposed to phenobarbital and/or dexamethasone, while eleven neonates were exposed to buprenorphine alone or in combination with phenobarbital. Patients were exposed to an average of 71.6 mg/kg (range 13.1 to 215 mg/kg) of ethanol after a single dose of an ethanol containing medication. Blood ethanol levels were detectable in 98% (38/39) of samples, quantifiable in 67% (26/39) of samples, and ranged from below detection to 85.4 mg/L. Ethanol was rapidly cleared and did not accumulate with current dosing regimens.
Ethanol intake secondary to medication administration varied widely. Blood ethanol levels in neonates were low and ethanol was eliminated rapidly after a single dose of oral medications that contained a sizable fraction of ethanol.
Adam E. Snook, Trevor R. Baybutt, Michael J. Mastrangelo, Nancy L. Lewis, Scott D. Goldstein, Walter K. Kraft, Yaa D. Oppong, Terry Hyslop, Ronald E. Myers, Vitali Alexeev, Laurence C. Eisenlohr, Takami Sato, and Scott A. Waldman
Ad5-GUCY2C-PADRE is a replication-deficient human type 5 recombinant adenovirus (Ad5) vaccine encoding guanylyl cyclase C (GUCY2C) fused to the PAn DR Epitope (PADRE). GUCY2C, a paracrine hormone receptor producing the second messenger cyclic GMP (cGMP), is selectively expressed by intestinal epithelial cells and a subset of hypothalamic neurons, but not other tissues. Importantly, GUCY2C is over-expressed in nearly all primary and metastatic human colorectal tumors. Preclinical studies in mice demonstrated selective tolerance of GUCY2C-specific CD4+ T cells, but not CD8+ T or B cells, necessitating inclusion of the exogenous CD4+ T helper cell epitope PADRE to maximize GUCY2C-specific CD8+ T-cell and antibody responses and antitumor efficacy, without autoimmunity.
Patients and Methods
This is an open-label, single arm “proof-of-concept” study evaluating a single dose level of Ad5-GUCY2C-PADRE as a vaccine for surgically-treated, node-negative colon cancer subjects (NCT01972737). Patients received a single intramuscular administration of 1011 Ad5-GUCY2C-PADRE viral particles. Safety and immunomonitoring were examined at 30, 90 and 180 days following vaccination. Primary objectives were to determine the safety, tolerability, and toxicity of Ad5-GUCY2C-PADRE and to determine whether Ad5- GUCY2C-PADRE induces GUCY2C-specific immune responses. The study employed a joint efficacy-toxicity design and included stopping rules for either efficacy or toxicity.Results here were obtained during the planned interim analysis following accrual of 10 subjects.
The vaccine was well tolerated, producing only mild adverse events (AEs). Short-lived injection site pain/swelling, body aches, and chills were the most commonly observed AEs and occurred in 30-40% of subjects. GUCY2C-specific antibody and T-cell responses were observed in a subset of subjects. Consistent with preclinical mouse data, T-cell responses were composed of CD8+, but not CD4+, T cells. Importantly, GUCY2C-specific responses occurred only in subjects with low Ad5 neutralizing antibody (NAb) titers at the time of vaccination, suggesting that pre-existing Ad5 immunity limits Ad5-GUCY2C-PADRE immunogenicity.
Interim analysis of 10 subjects receiving Ad5-GUCY2C-PADRE demonstrates proof-of-concept that GUCY2C is immunogenic in humans and that GUCY2C-directed vaccination is safe. Moreover, the presence of GUCY2C-specific antibody and CD8+ T-cell, but not CD4+ T-cell, responses is consistent with selective CD4+ T-cell tolerance observed in mouse models. These data establish GUCY2C as a safe and immunogenic target for immunotherapy in cancer patients.
Poster presented at: Immunotherapy of Cancer (SITC) 30th Annual Meeting in National Harbor Maryland.
Andrea L. Fielder, J. K. Coller, M. R. Hutchinson, Ross R. Haslam, Nona Lu, Susan C. Adeniyi-Jones, Michelle Ehrlich, and Walter K. Kraft
Poster presented at: CPDD Scientific Meeting, San Juan, PR.
Aims: NAS incidence & severity in infants exposed to methadone during gestation is independent of maternal methadone dose. The incidence & severity of NAS could be in part due to genetic variability of key genetic loci related to opioid response; the interleukin-1beta (IL-1B) & mu opioid receptor (OPRM1) genes. This study aimed to investigate the impact of genetic variability in IL-1B -31 or OPRM1 A118G on NAS incidence (treatment required) & severity (dose of morphine).
Methods: This pilot study collected cheek cells from 71 methadone exposed infants; 46 required treatment. Complete genetic & morphine treatment data were obtained for a subset of 26 NAS infants.
Results: There were no difference in IL-1B or OPRM1 genotypes between infants with, & without NAS (OR (p) = 1.9 (0.21) and 0.23 (0.24), respectively). There was also no impact of genetic variability at IL-1B and OPRM1 on morphine treatment (median, mg): initial morphine dose – wild-type (WT, n = 21) 0.15 and variant (Var, n = 5) 0.2 (p = 0.06) and WT (n = 24) 0.17 and Var (n = 2) 0.22 (p = 0.73), respectively; maximum morphine dose – WT (n = 21) 0.3 and Var (n = 5) 0.28 (p = 0.94) and WT (n = 24) 0.29 and Var (n = 2) 0.24 (p = 0.39), respectively; and total morphine in the first month of life – WT (n = 20) 33.8 and Var (n = 5) 34.8 (p = 0.67) and WT (n = 23) 34.8 and Var (n = 2) 25.4 (p = 0.38), respectively.
Conclusions: Despite genetic variability at these loci being reported to impact opioid response in adults, our study to date has not replicated these findings in infants. However, infant numbers in each genotype group were low. Therefore, the possibility remains for an association between genetic variability and NAS, leading to predictive tools to pre-determine NAS incidence & severity. Data collection for this project continues.