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== Human Study ==

===Phase 1 Study: First Human study of a chimeric anti-methamphetamine monoclonal antibody in healthy volunteers===

~~====Serum ch-mAb7F9 concentration====~~

~~====Immunogenicity analyses====~~

~~====IgG pharmacokinetic parameters====~~

~~half life 17-19 d, volume of distribution of 5-6 L in the 3 highest dose groups <ref name="First human study of a chimeric anti-methamphetamine monoclonal antibody in healthy volunteers " />~~

~~====Human anti-chimeric antibody response====~~

Four(12.5%) of the 32 subjects receiving ch-mAb7F9 were confirmed to have developed a human anti-chimeric antibody response by the end of the study (147 d);however, this response did not appear to be dose related.<ref name="First human study of a chimeric anti-methamphetamine monoclonal antibody in healthy volunteers " />

The first study is conducted in healthy 42 volunteers, 10s of which received saline placebo as control group.<ref name="First human study of a chimeric anti-methamphetamine monoclonal antibody in healthy volunteers/>. Single, escalating doses of ch-mAb7F9 over the range of 0.2 to 20mg/kg (5 dose groups) were administered and followed for 147 d for pharmacokinetic and immugenicity studies<ref name="First human study of a chimeric anti-methamphetamine monoclonal antibody in healthy volunteers"/>. No serious adverse reactions or discontinuations form the study due to adverse events<ref name="First human study of a chimeric anti-methamphetamine monoclonal antibody in healthy volunteers"/>. No trends emerged of adverse events<ref name="First human study of a chimeric anti-methamphetamine monoclonal antibody in healthy volunteers"/>. Half life of 17-19 d in the 3 highest does groups an volume of distribution of 5-6L suggesting antibody is confined primarily to the vascular compartment<ref name="First human study of a chimeric anti-methamphetamine monoclonal antibody in healthy volunteers"/>.

Serum ch-mAb7F9 concentration is plotted and reported for 147 d<ref name="First human study of a chimeric anti-methamphetamine monoclonal antibody in healthy volunteers"/>.

Most common AE include: increased blood creatine phosphokinase, upper respiratory tract infection, decreased hemoglobin, headache, increased aspartate aminotransferase and alanine aminotransferase, proteinuria, decreased white blood cell count, and nasal congestion<ref name="First human study of a chimeric anti-methamphetamine monoclonal antibody in healthy volunteers"/>. AEs considered by the investigator to be related to study medication were limited to single events in the 2mg/kg group <ref name="First human study of a chimeric anti-methamphetamine monoclonal antibody in healthy volunteers"/>and included infusion reaction, bronchospasm, and proteinuria<ref name="First human study of a chimeric anti-methamphetamine monoclonal antibody in healthy volunteers"/>. The 3 Grade 4 AEs(life-threatening) were all elevations in blood creatine phosphokinases levels and were considered unrelated to the ch-mAb and resolved without treatment. 6 events as Grade 3 and 47 grade 2 and 160 events as grade 1 (mild)<ref name="First human study of a chimeric anti-methamphetamine monoclonal antibody in healthy volunteers"/>.

Four(12.5%) of the 32 subjects receiving ch-mAb7F9 were confirmed to have developed a human anti-chimeric antibody response by the end of the study (147 d)<ref name="First human study of a chimeric anti-methamphetamine monoclonal antibody in healthy volunteers"/>;however, this response did not appear to be dose related.<ref name="First human study of a chimeric anti-methamphetamine monoclonal antibody in healthy volunteers " />

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After METH infusion 3.2mg/kg/day<ref name="Development and preclinical testing of a high-affinity single-chain antibody against (+)-methamphetamine"/> by osmotic minipumps which resulted average steady state serum concentration of 25ng/ml after 24h<ref name="Development and preclinical testing of a high-affinity single-chain antibody against (+)-methamphetamine"/>, mice were administered scFv6H4 which has led to drastic increase of serum concentration of METH<ref name="Development and preclinical testing of a high-affinity single-chain antibody against (+)-methamphetamine"/>, determined by liquid chromatography-tandem mass spectrometry as described previously<ref name ="Development of a liquid chromatography-tandem mass spectrometric method for the determination of methamphetamine and amphetamine using small volumes of rat serum"/>. The compare of the first 480 min METH concentration with control group was reported<ref name="Development and preclinical testing of a high-affinity single-chain antibody against (+)-methamphetamine"/>. scFv6H4 was reported stable in serum in vitro yet unstable in Urine in vitro<ref name="Development and preclinical testing of a high-affinity single-chain antibody against (+)-methamphetamine"/>. The concentration of scFv in serum in vivo was determined by SEC<ref name="Development and preclinical testing of a high-affinity single-chain antibody against (+)-methamphetamine"/>, the method has been previously described <ref name ="Pharmacokinetic mechanisms for obtaining high renal coelimination of phencyclidine and a monoclonal antiphencyclidine antigen-binding fragment of immunoglobulin G in the rat"/>. Monomer of scFv was reportd to have been completely eliminated in the serum within the first 30 minutes<ref name="Development and preclinical testing of a high-affinity single-chain antibody against (+)-methamphetamine"/>, yet the multivalent larger proteins persisted for >240 mins corresponding to the reported t1/2lamdaz to be 228 +/- 38 min<ref name="Development and preclinical testing of a high-affinity single-chain antibody against (+)-methamphetamine"/>. It is interesting that it was reported the divalent form did not decrease for the first 10 minutes, as if while it is been eliminated, it is also been formed from the mono scFvs. Pharmacokinetic parameters were reported for mono and multi scFvs respectively<ref name="Development and preclinical testing of a high-affinity single-chain antibody against (+)-methamphetamine"/>.

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@@ Line 163: / Line 163: @@
 == Human Study ==
 ===Phase 1 Study: First Human study of a chimeric anti-methamphetamine monoclonal antibody in healthy volunteers===
-====Serum ch-mAb7F9 concentration====
-====Immunogenicity analyses====
-====IgG pharmacokinetic parameters====
-half life 17-19 d, volume of distribution of 5-6 L in the 3 highest dose groups <ref name="First human study of a chimeric anti-methamphetamine monoclonal antibody in healthy volunteers " />
-====Human anti-chimeric antibody response====
-Four(12.5%) of the 32 subjects receiving ch-mAb7F9 were confirmed to have developed a human anti-chimeric antibody response by the end of the study (147 d);however, this response did not appear to be dose related.<ref name="First human study of a chimeric anti-methamphetamine monoclonal antibody in healthy volunteers " />
+The first study is conducted in healthy 42 volunteers, 10s of which received saline placebo as control group.<ref name="First human study of a chimeric anti-methamphetamine monoclonal antibody in healthy volunteers/>. Single, escalating doses of ch-mAb7F9 over the range of 0.2 to 20mg/kg (5 dose groups) were administered and followed for 147 d for pharmacokinetic and immugenicity studies<ref name="First human study of a chimeric anti-methamphetamine monoclonal antibody in healthy volunteers"/>. No serious adverse reactions or discontinuations form the study due to adverse events<ref name="First human study of a chimeric anti-methamphetamine monoclonal antibody in healthy volunteers"/>. No trends emerged of adverse events<ref name="First human study of a chimeric anti-methamphetamine monoclonal antibody in healthy volunteers"/>. Half life of 17-19 d in the 3 highest does groups an volume of distribution of 5-6L suggesting antibody is confined primarily to the vascular compartment<ref name="First human study of a chimeric anti-methamphetamine monoclonal antibody in healthy volunteers"/>.
+Serum ch-mAb7F9 concentration is plotted and reported for 147 d<ref name="First human study of a chimeric anti-methamphetamine monoclonal antibody in healthy volunteers"/>.
+Most common AE include: increased blood creatine phosphokinase, upper respiratory tract infection, decreased hemoglobin, headache, increased aspartate aminotransferase and alanine aminotransferase, proteinuria, decreased white blood cell count, and nasal congestion<ref name="First human study of a chimeric anti-methamphetamine monoclonal antibody in healthy volunteers"/>. AEs considered by the investigator to be related to study medication were limited to single events in the 2mg/kg group <ref name="First human study of a chimeric anti-methamphetamine monoclonal antibody in healthy volunteers"/>and included infusion reaction, bronchospasm, and proteinuria<ref name="First human study of a chimeric anti-methamphetamine monoclonal antibody in healthy volunteers"/>. The 3 Grade 4 AEs(life-threatening) were all elevations in blood creatine phosphokinases  levels and were considered unrelated to the ch-mAb and resolved without treatment. 6 events as Grade 3 and 47 grade 2 and 160 events as grade 1 (mild)<ref name="First human study of a chimeric anti-methamphetamine monoclonal antibody in healthy volunteers"/>.
+Four(12.5%) of the 32 subjects receiving ch-mAb7F9 were confirmed to have developed a human anti-chimeric antibody response by the end of the study (147 d)<ref name="First human study of a chimeric anti-methamphetamine monoclonal antibody in healthy volunteers"/>;however, this response did not appear to be dose related.<ref name="First human study of a chimeric anti-methamphetamine monoclonal antibody in healthy volunteers " />
@@ Line 197: / Line 193: @@
 After METH infusion 3.2mg/kg/day<ref name="Development and preclinical testing of a high-affinity single-chain antibody against (+)-methamphetamine"/> by osmotic minipumps which resulted average steady state serum concentration of 25ng/ml after 24h<ref name="Development and preclinical testing of a high-affinity single-chain antibody against (+)-methamphetamine"/>, mice were administered scFv6H4 which has led to drastic increase of serum concentration of METH<ref name="Development and preclinical testing of a high-affinity single-chain antibody against (+)-methamphetamine"/>, determined by liquid chromatography-tandem mass spectrometry as described previously<ref name ="Development of a liquid chromatography-tandem mass spectrometric method for the determination of methamphetamine and amphetamine using small volumes of rat serum"/>. The compare of the first 480 min METH concentration with control group was reported<ref name="Development and preclinical testing of a high-affinity single-chain antibody against (+)-methamphetamine"/>. scFv6H4 was reported stable in serum in vitro yet unstable in Urine in vitro<ref name="Development and preclinical testing of a high-affinity single-chain antibody against (+)-methamphetamine"/>. The concentration of scFv in serum in vivo was determined by SEC<ref name="Development and preclinical testing of a high-affinity single-chain antibody against (+)-methamphetamine"/>, the method has been previously described <ref name ="Pharmacokinetic mechanisms for obtaining high renal coelimination of phencyclidine and a monoclonal antiphencyclidine antigen-binding fragment of immunoglobulin G in the rat"/>. Monomer of scFv was reportd to have been completely eliminated in the serum within the first 30 minutes<ref name="Development and preclinical testing of a high-affinity single-chain antibody against (+)-methamphetamine"/>, yet the multivalent larger proteins persisted for >240 mins corresponding to the reported t1/2lamdaz to be 228 +/- 38 min<ref name="Development and preclinical testing of a high-affinity single-chain antibody against (+)-methamphetamine"/>. It is interesting that it was reported the divalent form did not decrease for the first 10 minutes, as if while it is been eliminated, it is also been formed from the mono scFvs. Pharmacokinetic parameters were reported for mono and multi scFvs respectively<ref name="Development and preclinical testing of a high-affinity single-chain antibody against (+)-methamphetamine"/>.