Pharmacokinetics and Pharmacodynamics of Antibody-Drug Conjugates Administered via Subcutaneous and Intratumoral Routes
We hypothesize that different routes of administration may lead to altered pharmacokinetics/pharmacodynamics (PK/PD) behavior of antibody-drug conjugates (ADCs) and may help to improve their therapeutic index. To evaluate this hypothesis, here we performed PK/PD evaluation for an ADC administered vi...
| Main Authors: | , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-04-01
|
| Series: | Pharmaceutics |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1999-4923/15/4/1132 |
| _version_ | 1797603880424439808 |
|---|---|
| author | Hsuan-Ping Chang Huyen Khanh Le Dhaval K. Shah |
| author_facet | Hsuan-Ping Chang Huyen Khanh Le Dhaval K. Shah |
| author_sort | Hsuan-Ping Chang |
| collection | DOAJ |
| description | We hypothesize that different routes of administration may lead to altered pharmacokinetics/pharmacodynamics (PK/PD) behavior of antibody-drug conjugates (ADCs) and may help to improve their therapeutic index. To evaluate this hypothesis, here we performed PK/PD evaluation for an ADC administered via subcutaneous (SC) and intratumoral (IT) routes. Trastuzumab-vc-MMAE was used as the model ADC, and NCI-N87 tumor-bearing xenografts were used as the animal model. The PK of multiple ADC analytes in plasma and tumors, and the in vivo efficacy of ADC, after IV, SC, and IT administration were evaluated. A semi-mechanistic PK/PD model was developed to characterize all the PK/PD data simultaneously. In addition, local toxicity of SC-administered ADC was investigated in immunocompetent and immunodeficient mice. Intratumoral administration was found to significantly increase tumor exposure and anti-tumor activity of ADC. The PK/PD model suggested that the IT route may provide the same efficacy as the IV route at an increased dosing interval and reduced dose level. SC administration of ADC led to local toxicity and reduced efficacy, suggesting difficulty in switching from IV to SC route for some ADCs. As such, this manuscript provides unprecedented insight into the PK/PD behavior of ADCs after IT and SC administration and paves the way for clinical evaluation of these routes. |
| first_indexed | 2024-03-11T04:38:15Z |
| format | Article |
| id | doaj.art-69d67a523994457c9d0fe5d412c7292b |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-11T04:38:15Z |
| publishDate | 2023-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-69d67a523994457c9d0fe5d412c7292b2023-11-17T20:53:11ZengMDPI AGPharmaceutics1999-49232023-04-01154113210.3390/pharmaceutics15041132Pharmacokinetics and Pharmacodynamics of Antibody-Drug Conjugates Administered via Subcutaneous and Intratumoral RoutesHsuan-Ping Chang0Huyen Khanh Le1Dhaval K. Shah2Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, The State University of New York at Buffalo, Buffalo, NY 14241, USADepartment of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, The State University of New York at Buffalo, Buffalo, NY 14241, USADepartment of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, The State University of New York at Buffalo, Buffalo, NY 14241, USAWe hypothesize that different routes of administration may lead to altered pharmacokinetics/pharmacodynamics (PK/PD) behavior of antibody-drug conjugates (ADCs) and may help to improve their therapeutic index. To evaluate this hypothesis, here we performed PK/PD evaluation for an ADC administered via subcutaneous (SC) and intratumoral (IT) routes. Trastuzumab-vc-MMAE was used as the model ADC, and NCI-N87 tumor-bearing xenografts were used as the animal model. The PK of multiple ADC analytes in plasma and tumors, and the in vivo efficacy of ADC, after IV, SC, and IT administration were evaluated. A semi-mechanistic PK/PD model was developed to characterize all the PK/PD data simultaneously. In addition, local toxicity of SC-administered ADC was investigated in immunocompetent and immunodeficient mice. Intratumoral administration was found to significantly increase tumor exposure and anti-tumor activity of ADC. The PK/PD model suggested that the IT route may provide the same efficacy as the IV route at an increased dosing interval and reduced dose level. SC administration of ADC led to local toxicity and reduced efficacy, suggesting difficulty in switching from IV to SC route for some ADCs. As such, this manuscript provides unprecedented insight into the PK/PD behavior of ADCs after IT and SC administration and paves the way for clinical evaluation of these routes.https://www.mdpi.com/1999-4923/15/4/1132intratumoral administrationsubcutaneous administrationantibody-drug conjugate (ADC)local toxicitymonomethyl auristatin E (MMAE)pharmacokinetics/pharmacodynamics (PK/PD) |
| spellingShingle | Hsuan-Ping Chang Huyen Khanh Le Dhaval K. Shah Pharmacokinetics and Pharmacodynamics of Antibody-Drug Conjugates Administered via Subcutaneous and Intratumoral Routes Pharmaceutics intratumoral administration subcutaneous administration antibody-drug conjugate (ADC) local toxicity monomethyl auristatin E (MMAE) pharmacokinetics/pharmacodynamics (PK/PD) |
| title | Pharmacokinetics and Pharmacodynamics of Antibody-Drug Conjugates Administered via Subcutaneous and Intratumoral Routes |
| title_full | Pharmacokinetics and Pharmacodynamics of Antibody-Drug Conjugates Administered via Subcutaneous and Intratumoral Routes |
| title_fullStr | Pharmacokinetics and Pharmacodynamics of Antibody-Drug Conjugates Administered via Subcutaneous and Intratumoral Routes |
| title_full_unstemmed | Pharmacokinetics and Pharmacodynamics of Antibody-Drug Conjugates Administered via Subcutaneous and Intratumoral Routes |
| title_short | Pharmacokinetics and Pharmacodynamics of Antibody-Drug Conjugates Administered via Subcutaneous and Intratumoral Routes |
| title_sort | pharmacokinetics and pharmacodynamics of antibody drug conjugates administered via subcutaneous and intratumoral routes |
| topic | intratumoral administration subcutaneous administration antibody-drug conjugate (ADC) local toxicity monomethyl auristatin E (MMAE) pharmacokinetics/pharmacodynamics (PK/PD) |
| url | https://www.mdpi.com/1999-4923/15/4/1132 |
| work_keys_str_mv | AT hsuanpingchang pharmacokineticsandpharmacodynamicsofantibodydrugconjugatesadministeredviasubcutaneousandintratumoralroutes AT huyenkhanhle pharmacokineticsandpharmacodynamicsofantibodydrugconjugatesadministeredviasubcutaneousandintratumoralroutes AT dhavalkshah pharmacokineticsandpharmacodynamicsofantibodydrugconjugatesadministeredviasubcutaneousandintratumoralroutes |