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Report for Clinical Trial NCT03781752

Developed by Shray Alag, 2020.
SNP Clinical Trial Gene

Carboxylesterase 1 Genetic Variation and Methylphenidate in ADHD

The study team will determine the association between d,l-methylphenidate (MPH) therapeutic outcomes in ADHD patients and genetic variants of CES1 and reveal key associations between CES1 genotypes and the PK and PD of MPH.

NCT03781752 ADHD Attention Deficit Hyperactivity Disorder
MeSH:Attention Deficit Disorder with Hyperactivity
HPO:Attention deficit hyperactivity disorder

1 Interventions

Name: Methylphenidate

Description: study to determine dose
Type: Drug
Group Labels: 1

Methylphenidate


Primary Outcomes

Description: The maximum plasma concentration achieved after dosing.

Measure: Maximum methylphenidate plasma concentration (Cmax),

Time: up to 8 Hours

Secondary Outcomes

Description: The time after administration of a drug when the maximum plasma concentration is reached; when the rate of absorption equals the rate of elimination.

Measure: Time to maximum concentration (Tmax)

Time: up 8 hours

Description: Area under the plasma concentration-time curve from time zero to the last measurable concentration.

Measure: Area under the plasma concentration curve (AUClast)

Time: up to 8 hours

Description: Area under the plasma concentration-time curve from time zero to infinity.

Measure: Area under the plasma concentration curve (AUCinf)

Time: up to 8 hours

Purpose: Basic Science

Allocation: N/A

Single Group Assignment


There are 2 SNPs

SNPs


1 D203E

In addition, the study team's in vitro studies have revealed that another common CES1 variant D203E (rs2307227) exhibited significantly impaired activity on MPH metabolism, although the effects on D203E on clinical response are in need of further elucidation. --- D203E ---

In addition, the study team's in vitro studies have revealed that another common CES1 variant D203E (rs2307227) exhibited significantly impaired activity on MPH metabolism, although the effects on D203E on clinical response are in need of further elucidation. --- D203E --- --- D203E ---

The study team's hypothesis is that the CES1 variants, such as the G143E and D203E, can significantly alter the expression and/or activity of CES1, thereby influencing the metabolism and disposition of MPH. --- G143E --- --- D203E ---


2 G143E

The first clinically significant CES1 variant G143E (rs71647871), discovered in the study team's lab during the course of a healthy volunteer MPH PK study, led to gross impairments in MPH metabolism. --- G143E ---

The study team has established the minor allele frequency (MAF) of the G143E variant as 3-4% in the general population. --- G143E ---

G143E carrier's frequency 6-8%) with a genetically impaired ability to metabolize/deactivate the drug will receive it - exposing them to high systemic concentrations of MPH and any attendant risks or toxicities. --- G143E ---

The study team's hypothesis is that the CES1 variants, such as the G143E and D203E, can significantly alter the expression and/or activity of CES1, thereby influencing the metabolism and disposition of MPH. --- G143E ---



HPO Nodes


HPO:
HP:0007018: Attention deficit hyperactivity disorder
Genes 280
TRNF MID2 MKRN3-AS1 ACTL6B PTCHD1 SYNJ1 UBE3A TRAK1 CXORF56 SMPD1 USP7 CLTC FLI1 SMC3 FGF12 BCR KCNB1 TBX1 ARHGEF6 TRIO PAH DHTKD1 SLITRK1 KIF14 YWHAG SIN3A CHD7 PWRN1 TRNL1 SETD5 PPM1D LIMK1 OCRL TBL2 CRBN KIF11 ARF1 HCFC1 SLC1A2 KCNA2 USP9X STS CNKSR2 ALKBH8 SH3KBP1 RPS20 DPH1 TAF1 DYNC1I2 YY1 HDAC8 CIC SLC9A7 IKBKG TSPAN7 TBX1 NR2F1 ALG13 HERC2 ND1 TKT KMT2A SLC6A8 TMCO1 PRKCG COX2 HIRA GNE RAI1 GABRA1 LIG4 SH2B1 SIM1 SEMA4A MED12 RAD21 GABRB2 GDI1 TBC1D24 UFD1 GRIA4 PHIP CLIP2 IL1RAPL1 SATB2 SETD5 NBN NIPBL CACNA1A GNE CSNK2A1 PCGF2 SH2B1 TRNQ PRNP NDP SIN3A CNKSR2 JMJD1C SRPX2 DNM1 CPLX1 IFNG AUTS2 ARID2 HSPG2 GRIN2A THRB SNORD116-1 MLH1 IPW GABRA5 STAG2 GABRB3 BMPR1A ZDHHC9 DHCR7 HDC ACSL4 GLUD1 TRNS1 FGD1 PMS1 CLCN4 TSC1 KCNA2 SOX5 HOXA2 MAP11 SEC24C SLC2A1 ADNP SMC1A MSH6 EEF1A2 FLII NOP56 MKRN3 PIK3CA ATP6V1A CACNA1H PAH HCN1 CACNA1B DLG3 GRIN2D GABRG2 IQSEC2 EPCAM CHRNA7 UPF3B NDN PAK3 ABCD1 IQSEC2 KRAS MCTP2 C12ORF4 SNORD115-1 TSC2 TLK2 PMS2 TSC2 PPP3CA SYP BCORL1 COMT SZT2 PCNT ARVCF GTF2I VPS13A FTSJ1 TRNW COX3 TGFBR2 ASPM GNB5 SPG7 ZNF41 UPF3B RERE SYNGAP1 STS GATA4 DRD5 OPHN1 TRNH COX1 GNAQ ELN AGTR2 TBX1 LHCGR FGFR3 YWHAG TBX1 ND5 DNAJC12 AP3B2 FGD1 ND4 DHDDS PTCHD1 TRNS2 UBA5 CNKSR2 MLXIPL USP27X HDAC4 RAI1 MAGEL2 DMD ELN SNRPN NUS1 RSRC1 WAC TRIO PWAR1 ARV1 RREB1 TIMM8A ARX NPAP1 GABRG2 BAZ1B TUBB2B FAN1 SPRED1 WWOX POLA1 DEAF1 SCN8A SETBP1 SLC13A5 STXBP1 DPP6 GABRG2 RAI1 DRD4 SCN8A DYM ZNF711 PARS2 GP1BB JRK TKT CYFIP2 AARS1 MSH2 RFC2 PIEZO2 MAPK1 NTRK2 MED12 NSUN2 FRMPD4 MED12 GRIN2A PANK2 RAB39B MLH3 FOXP1 ND6 SCN3A RPS6KA3 CRKL FMR1 IGF1 MECP2 SEMA3E RERE NECAP1 GTF2IRD1 ZNF81 MED12 CLTC TSC1 GABRA2
Protein Mutations 2
D203E G143E