Chapter - Use of PK/PD Assessments for Selecting the Best ACTs | Bentham Science

Pharmacokinetics and Pharmacodynamics of Antimalarial Drugs Used in Combination Therapy

Author(s): Qigui Li and Mark R. Hickman

DOI: 10.2174/9781681080543115010010

Use of PK/PD Assessments for Selecting the Best ACTs

Pp: 219-265 (47)

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Pharmacokinetics and Pharmacodynamics of Antimalarial Drugs Used in Combination Therapy

Use of PK/PD Assessments for Selecting the Best ACTs

Author(s): Qigui Li and Mark R. Hickman

Pp: 219-265 (47)

DOI: 10.2174/9781681080543115010010

* (Excluding Mailing and Handling)

Abstract

Most of the antimalarial drugs and their combination formulations in current use came on market before the modern use of PK and PD principles for dosage design to maximize drug efficacy. Antimalarial dose regimens have been empirical in nature based on clinical studies with drug half-life, PK inter-individual variation, drug exposure level and time variables have been derived from experimental data or referred to by data from public trials. PK studies involve investigating the relationship between drug absorption, distribution, metabolism, and excretion, while PD studies investigate relationships between the drug target and the drug itself, the mechanism by which the drug works, and the clinical effect the drug provides. Both kinds of studies are involved when assessing drug interactions. Many drugs are metabolized into a similar metabolism pathway or shared an identical target that provides an opportunity to match the proper partner drugs for an antimalarial combination. The ideal PK properties of antimalarial drugs have long been deliberated. From a perspective of preventing drug resistance, drug combination partners should have a similar PK profile. The implications of a PD mismatch on ACTs are not clear at present, particularly in regions with high malaria transmission. Current recommended ACTs have repeatedly shown in a variety of clinical studies that the PD match between ACT partner drugs is good, the combinations are efficacious, well-tolerated, and provide protection against new infections. As discussed in other chapters, PK/PD mismatched ACTs have a known risk of encouraging drug resistance to partner drugs where drug resistance has yet to emerge, and drug combinations that are mismatched will not aid in the important public health job of limiting the spread of resistance.


Keywords: Chemoprophylaxis, chemotherapy, clinical trials, combination, combination partner, dosage design, dosage regimen, metabolism matching, PD matching, PD mismatch, PK matching, PK mismatch, PK/PD mismatch.

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      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Trial Access" as access_base_text, CASE j.type WHEN 111 THEN true ELSE false END as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"chapter" as access_level, j.chapter_id from `user_access_chapter_trail` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 59830868 and j.to_ip >=59830868 )) and ((j.from_date <= 1736178371 and j.to_date >= 1736178371 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.chapter_id = 7631) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Subscribed" as access_base_text, false as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"chapter" as access_level, j.chapter_id from `user_access_chapter_corporate` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 59830868 and j.to_ip >=59830868 )) and ((j.from_date <= 1736178371 and j.to_date >= 1736178371 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.chapter_id = 7631) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Token Based Access" as access_base_text, false as terms_popup, "R" as content_download_type, j.uc_id as restricted_user_access_key, "v" as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"chapter" as access_level, j.chapter_id from `user_access_chapter_token` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 59830868 and j.to_ip >=59830868 )) and ((j.from_date <= 1736178371 and j.to_date >= 1736178371 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.chapter_id = 7631)
      520μsalphaeurekaselec_live_10_06_2022UserAccess.php#1266
      Backtrace
      • 13. app/Models/UserAccess/UserAccess.php:1266
      • 14. app/Http/Controllers/ChapterController.php:1548
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select b.banner_link, b.banner_name, b.banner_script, b.banner_remarks, b.banner_file_name, b.banner_placement, bd.content_type, bd.content_id from `tbl_banner` as `b` inner join `tbl_banner_detail` as `bd` on `bd`.`banner_id` = `b`.`banner_id` inner join `users` as `u` on `u`.`id` = `b`.`updated_by` where `b`.`banner_ebook` = 1 and `bd`.`content_type` = 'B' and `bd`.`content_id` = 1724 and `b`.`banner_from_date` <= 1736178371 and `b`.`banner_to_date` >= 1736178371 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.02msalphaeurekaselec_live_10_06_2022Banner.php#189
      Bindings
      • 0: 1
      • 1: B
      • 2: 1724
      • 3: 1736178371
      • 4: 1736178371
      • 5: A
      Backtrace
      • 13. app/Models/Banner.php:189
      • 14. app/Http/helpers.php:404
      • 17. vendor/laravel/framework/src/Illuminate/Filesystem/Filesystem.php:124
      • 18. vendor/laravel/framework/src/Illuminate/View/Engines/PhpEngine.php:58
      • 19. vendor/laravel/framework/src/Illuminate/View/Engines/CompilerEngine.php:73
    • select count(*) as aggregate from `uc_cart_products` where cart_id='8a415b7518bd4ae75abc3895efb1fcf2'
      190μsalphaeurekaselec_live_10_06_2022Cart.php#271
      Backtrace
      • 15. app/Models/Cart.php:271
      • 16. view::layouts._main_menu:13
      • 18. vendor/laravel/framework/src/Illuminate/Filesystem/Filesystem.php:124
      • 19. vendor/laravel/framework/src/Illuminate/View/Engines/PhpEngine.php:58
      • 20. vendor/laravel/framework/src/Illuminate/View/Engines/CompilerEngine.php:73
    App\Models\Keywords
    13Keywords.php#?
    App\Models\Chapter
    1Chapter.php#?
    App\Models\Ebook
    1Ebook.php#?
        _token
        gj7D9aEbOI4kzFvSYPmOVthwQ9secqW4hyT2minQ
        uc_cart_id
        8a415b7518bd4ae75abc3895efb1fcf2
        _previous
        array:1 [ "url" => "https://beta.benthamscience.com/chapter/7631" ]
        _flash
        array:2 [ "old" => [] "new" => [] ]
        PHPDEBUGBAR_STACK_DATA
        []
        path_info
        /chapter/7631
        status_code
        200
        
        status_text
        OK
        format
        html
        content_type
        text/html; charset=UTF-8
        request_query
        []
        
        request_request
        []
        
        request_headers
        0 of 0
        array:16 [ "x-https" => array:1 [ 0 => "1" ] "host" => array:1 [ 0 => "beta.benthamscience.com" ] "priority" => array:1 [ 0 => "u=0, i" ] "accept-encoding" => array:1 [ 0 => "gzip, deflate, br, zstd" ] "sec-fetch-dest" => array:1 [ 0 => "document" ] "sec-fetch-user" => array:1 [ 0 => "?1" ] "sec-fetch-mode" => array:1 [ 0 => "navigate" ] "sec-fetch-site" => array:1 [ 0 => "none" ] "accept" => array:1 [ 0 => "text/html,application/xhtml+xml,application/xml;q=0.9,image/avif,image/webp,image/apng,*/*;q=0.8,application/signed-exchange;v=b3;q=0.7" ] "user-agent" => array:1 [ 0 => "Mozilla/5.0 AppleWebKit/537.36 (KHTML, like Gecko; compatible; ClaudeBot/1.0; +claudebot@anthropic.com)" ] "upgrade-insecure-requests" => array:1 [ 0 => "1" ] "sec-ch-ua-platform" => array:1 [ 0 => ""Windows"" ] "sec-ch-ua-mobile" => array:1 [ 0 => "?0" ] "sec-ch-ua" => array:1 [ 0 => ""HeadlessChrome";v="129", "Not=A?Brand";v="8", "Chromium";v="129"" ] "cache-control" => array:1 [ 0 => "no-cache" ] "pragma" => array:1 [ 0 => "no-cache" ] ]
        request_cookies
        []
        
        response_headers
        0 of 0
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        session_attributes
        0 of 0
        array:5 [ "_token" => "gj7D9aEbOI4kzFvSYPmOVthwQ9secqW4hyT2minQ" "uc_cart_id" => "8a415b7518bd4ae75abc3895efb1fcf2" "_previous" => array:1 [ "url" => "https://beta.benthamscience.com/chapter/7631" ] "_flash" => array:2 [ "old" => [] "new" => [] ] "PHPDEBUGBAR_STACK_DATA" => [] ]
        ClearShow all
        Date ↕MethodURLData
        #12025-01-06 15:46:11GET/chapter/76311111915