Safety, efficacy and pharmacokinetics profile of antimalarial drugs in pregnancy : pharmacoepidemiology studies

Background: Malaria in pregnancy is an important public health problem in sub Saharan Africa. It is known to be the most common and preventable cause of harmful birth outcomes in malaria endemic areas. It is therefore important for a pregnant woman to be treated with safe and effective antimalarial medication. Drug safety in pregnancy is of a greater concern due to limited safety data available in this vulnerable group. This is because pregnant women are not involved in clinical trials related to drug development process due to safety reasons and hence, most of these medicines come to market with limit information available about their safety in pregnancy. Hence, establishing a drug safety monitoring mechanism would be important to generate safety data when a given medicine is already in the market, especially medications against tropical diseases.
Pregnant women are at increased risk of malaria infection and illness than non-pregnant individuals due to physiological, hormonal and immunological changes that occur in their body after conception. The changes are also responsible for various therapeutic challenges that face this vulnerable group. This explains the presence of significant alteration of antimalarial pharmacokinetic (PK) properties in pregnancy and hence lead to a reduced drug blood concentration, which will ultimately lower antimalarial cure rate. Another factor that affects antimalarial effectiveness in pregnancy is parasite resistance against sulfadoxine-pyrimethamine (SP), a drug that is used for intermittent preventive treatment of malaria in pregnancy (IPTp).
The objectives of the thesis were to assess the magnitude of drugs exposure during pregnancy in relation to pregnancy outcomes, to describe the feasibility of establishing active pharmacovigilance system in developing countries using Health Demographic Surveillance System (HDSS) platform, to determine safety of artemether-lumefantrine (AL) exposure in first trimester of pregnancy, to evaluate pharmacokinetics and pharmacodynamics properties of artemether-lumefantrine in pregnant and non-pregnant women, and to determine the effectiveness of IPTp-SP in prevention of placental malaria, maternal anaemia and low birth weight in areas with different malaria transmission intensity.
Method: Three different study designs were used independently to respond to different specific objectives of this thesis; (i) a longitudinal follow up study was conducted to generate artemether/lumefantrine (AL) safety data in first trimester secondary to its inadvertent exposure in two Health Demographic Surveillance System (HDSS) areas in Tanzania. Pregnant women with gestational age ? 20 weeks were enrolled and followed up on monthly bases until delivery. Drugs exposures during the entire pregnancy period were also recorded. The latter was used to document the feasibility of establishing active pharmacovigilance system using HDSS platform in one of the studied HDSS area. (ii) To determine AL PK, a prospective study involving pregnant in second and third trimester and non-pregnant women, both with uncomplicated P falciparum malaria. Plasma samples were collected at pre-defined dates for bioassay to determine drug level. Participants were followed up on pre-defined schedule visits until day 42. Inter- and intra-individual variability was assessed and covariated effects quantified using a nonlinear mixed-effect modeling approach (NONMEM®). (iii) Another prospective study enrolling pregnant women to assess the effectiveness of IPTp in two areas with different malaria transmission intensity. Pregnant women were recruited in the labor ward and structured questionnaire was used for interview. Placental parasitaemia was screened by using both light microscope and real-time quantitative PCR.
Findings
Pharmacovigilance system
91% (994 of 1089) of pregnant women who were piloted to assess feasibility of establishing active PV system completed the follow up until delivery. 98% of pregnant women reported to have taken at least one medication during pregnancy, mainly drugs provided in the antenatal program. Other most reported drugs were analgesics (24%), antibiotics (17%) and antimalarials (15%), excluding IPTp. Iron and folate supplementations were associated with decreased risk of miscarriage/stillbirth (OR 0.1; 0.08 – 0.3).
AL safety
82% (1783 of 2167) of pregnant women who used and not used antimalarial drugs in first trimester were followed until delivery and recorded their pregnancy outcome. 319 (17.9%) used antimalarial drugs in first trimester and AL was the most frequent antimalarial used [53.9% (172 of 319)]. Others were 24.4 % quinine, 20.7% SP and 3.4% amodiaquine. Quinine exposure in first trimester was associated with increased risk of miscarriage/stillbirth (OR 2.5; 1.3 – 5.1) and premature birth (OR 2.6; 1.3 – 5.3). AL, SP and amodiaquine exposure were found not to be harmful.
PK analysis
33 pregnant women and 22 non-pregnant women with malaria were treated with AL (80/480mg) twice daily for 3 days. Lumefantrine (LF) bioavailability and metabolism rate into desmethyl-lumefantrine were respectively 34% lower and 78% higher in pregnant than in non-pregnant patients. Overall PCR uncorrected therapeutic failure was 18% in pregnant and 5% in non-pregnant women (OR 4.0; p value 0.22). A higher median day 7 LF concentration was associated with adequate clinical and parasitological response.
Effectiveness of IPTp
350 pregnant women were recruited and screened for placental parasitaemia (175 each from high and low malaria transmission areas). Prevalence of placenta parasitaemia was 16.6% in high transmission area and 2.3% in low transmission area. One or more doses of IPTp in high transmission area had 80% impact against placental malaria (OR 0.2; CI 0.06 – 0.7; p=0.015) and 60% in low transmission (OR 0.4; CI 0.04 – 4.5; p=0.478). Primigravida and residing in high transmission area were significant risk factors for placental malaria (OR 2.4; CI 1.1 – 5.0) and (OR 9.4; CI 3.2 – 27.7), respectively. The numbers needed to treat (NNT) was 4 (CI 2 – 4) women in high transmission area and 33 (CI 20 – 50) low transmission area to prevent one placental malaria. IPTp use was not statistically significant associated with decreased risk of maternal anaemia or low birth weight, regardless are of transmission intensity.
Conclusion:
Overall medicine use in pregnancy period is very high, including AL exposure in first trimester albeit this drug is not the first line treatment for malaria in early pregnancy. AL use in first trimester was safer as opposed to quinine, the first line drug which was associated with adverse pregnancy outcomes. We therefore recommend to consider other options than quinine for standard antimalarial drug in first trimester, and AL could be the best one.
HDSS platforms represent a reliable and feasible support to build on a pharmacovigilance system to assess safety of drugs in pregnancy since it has proved to be feasible. We recommend that pharmaceutical companies and other global financial bodies should invest more on the establishment of active pharmacovigilance system in pregnancy in tropical developing countries. The latter will boost safety data pool of newly marketed medicines and anti-infective agents for treating different illnesses in pregnancy.
LF bioavailability is significantly lowered in pregnant women due to altered PK properties as opposed to non-pregnant women in the same area. This may be responsible for therapeutic failure among pregnant women secondary to the observed low post-treatment prophylaxis. We recommend to evaluate a modified treatment regimen of malaria in pregnancy. ---------- Muhtasari
Utangulizi: Ugonjwa wa malaria kwa mama mjamzito ni tatizo kuu kwenye afya ya jamii hasa Africa kusini mwa jangwa la Sahara. Malaria ni miongoni mwa magonjwa yanayoweza kuzuilika. Ugonjwa huu unasababisha mazara makubwa sana kwa mtoto mchanga tokea akiwa tumboni kwa mama yake hasa sehemu zenye malaria kwa kiwango cha juu. Hivyo basi ni vema mama mjamzito atibiwe na dawa salama na zenye uwezo mkubwa wa kuangamiza vidudu vya malaria. Usalama wa dawa kwa mama mjamzito ni kitu chenye changamoto kubwa kutokana na uhaba wa takwimu muhimu za usalama wa dawa za malaria kwa wajawazito. Sababu kuu inatokana na mama wajawazito kutohusishwa kwenye majaribio ya dawa kipindi cha za mwanzoni pale ambapo dawa husika bado hazijapewa kibali cha kuingia sokoni kwa sababu ya kuhofia usalama wa kiafya hasa kwa mtoto aliyopo tumboni. Hilo linapelekea kwa dawa nyingi kuingia sokoni zikiwa na upungufu wa taarifa muhimu juu ya usalama wake kwa mama mjamzito. Kwa sababu hiyo, ni muhimu kuwa na mfumo wa kipekee wa kumfuatilia mama mjamzito pale atakapotumia dawa ambazo zipo tayari sokoni ili kuboresha taarifa za kiusalama kiafya kutokana na matumizi yake kipindi cha ujauzito.
Mama mjamzito anahatari kubwa ya kuambukizwa ugonjwa wa malaria pamoja na kuuguwa kuliko mama ambaye hana ujauzito. Hili linatokana na mabadiliko kipindi cha ujauzito ambayo yanasababishwa na kupunguwa kwa kinga ya mwili na mabadiliko ya homoni mwilini mwake. Mabadiliko haya yanachangia pia kuathiri ufanisi wa dawa mwilini kwake kupambana na vijidudu vya malaria na hivyo kupunguza uwezo wa uponyaji. Usugu wa dawa dhidi ya vijidudu vya malaria, kwa mfano dawa ya SP huchangia pia kuathiri uwezo wa kumponya mgonjwa wa malaria.
Dhumini kuu la utafiti huu ni (i) kujuwa wingi wa dawa anazotumia mama mjamzito ukilinganisha na matokeo ya mimba yake, (ii) kuonyesha uwezekano wa kuwa na mfumo pekee wa kudhibitisha matumizi ya dawa ambao utaweza kufuatilia usalama na matumizi ya dawa kwa ujumla kwa mama mjamzito, kwenye nchi inayoendelea kwa kutumia mfumo wa HDSS (Health Demographic Surveillance System), (iii) kuhakiki usalama wa matumizi ya dawa mseto (ALU) ya malaria kipindi cha mimba changa, (iv) kutathimini unyambulisho wa dawa ya mseto mwilini mwa mgonjwa sambamba na kulinganisha ufanisi wake wa kuangamiza vijidudu vya malaria, na (v) kutathimini ufanisi wa dawa ya SP ambayo mama mjamzito anapatiwa kliniki kama inasaidia kuangamiza vijidudu vya malari kwenye kondo la uzazi, kuzuia upungufu wa damu kwa mama na mtoto kutozaliwa na kilo pungufu kwenye maeneo yenye viwango tofauti vya maambukizo ya malaria.
Methodolojia: Njia tatu tofauti zilitumika kupata majibu husika ya malengo ya utafiti huu; (i) Kufuatilia mama wajawazito tokea kipindi cha mwanzo cha ujauzito wao hadi wanapojifungua na kurekodi taarifa za matumizi ya dawa (ikiwemo dawa mseto) na matokeo ya ujauzito. Zoezi hili lilifanyika kwenye vituo vya HDSS huko Rufiji na Kigoma mjini. (ii) Unyambulisho wa ufanisi wa dawa mseto uliwahusisha wanawake ambao ni wajawazito (wenye umri wa mimba kuanzia wiki 13 na kuendelea) na wale wasio wajawazito lakini wote wakiwa wametambulika hawana malaria kali. Walipewa dawa mseto na kutolewa damu kwa kipindi tofauti tofauti ndani ya siku 42 za kuwafuatilia ili kupima kiwango cha dawa kwenye damu na kuhakiki vijidudu vya malaria vinavyo angamia. (iii) Kuhakiki ufanisi wa SP kama kinga ya malaria kwa mama mjamzito (IPTp) ilihusisha kuwatambua akina mama wajawazito wakiwa kwenye hospitali mbili tofauti ambazo zipo kwenye maeneo yanye viwango tofauti vya uambukizaji wa malaria. Utambuzi wa akinamama hawa ulikuwa muda mfupi kabla hawajajifungua na ulihusisha kukusanya damu toka kwenye kondo la uzazi mara tu baada ya kujifungua na kupima kama kuna maambukizi ya vijidudu vya malaria.
Matokea: (i) Mfumo wa ukusanyaji taarifa ya matumizi ya dawa kipindi chote cha ujauzito. Asilimia 90 (994/1089) ya mama wajawazito waliweza kufuatiliwa mpaka walipo jifunguwa. Jumla ya 98% waliripoti kutumia walau aina moja ya dawa kipindi cha ujauzito, hasa zikiwa dawa zinazotolewa kwenye mpango maalumu wa mama na mtoto. Dawa nyingi zikiwa ni dawa za kuzuia maumivu (24%), antibayotiki (17%) na dawa za kutibu malaria (15%). Imeonekana dawa za kuongeza wingi wa dama zinahusiana na kupunguza hatari ya mimba kuharibika na mtoto kuzaliwa njiti.
(ii) Usalama wa dawa mseto: Jumla ya mama wajawazito 1783 kati ya 2167 (82%) waliyotumia na ambao hawajatumia dawa za malaria kipindi cha miezi mitatu ya mwanzo ya ujauzito walifuatiliwa na kurekodi matokeo yao ya ujauzito wao. 319 (17.9%) walitumia dawa za malaria kipindi hicho cha mwanzo cha ujauzito na kati ya hawa 53.9% walitumia dawa mseto. Wengine walitumia quinine (24.4%), SP (20.7%) na amodiaquine (3.4%). Matumizi ya quinine kipindi cha miezi mitatu ya mwanzo ya mimba yalihusishwa na kuharibika kwa mimba na kuzaa mtoto njiti. Dawa ya mseto, SP na amodiaquine zilionyesha kutokuwa na mathara yeyote.
(iii) Unyambulisho wa ufanisi ya dawa mseto: Utafiti huu ulihusisha wajawazito 33 na wanawake wasio wajawazito 22 waliyo na malaria na kutibiwa na dozi kamili ya dawa mseto mara mbili kutwa kwa siku 3. Sehemu ya dawa ya mseto ilionekana kuwa pungufu kwa wajawazito ukilinganisha na wale wasiyo wajawazito. Kwenye kipindi cha kuwafuatiliya wagonjwa (ndani ya siku 42), 18% ya wajawazito na 5% ya wasiyo wajawazito waligundulika kuwa bado wana vijidudu vya malaria. Kuwa na kiwango kikubwa cha dawa ya mseto kwenye mzunguko wa damu ulihusishwa na kupona malaria kwa ufasaha.
(iv) Ufanisi wa SP kama kinga ya malaria kwa mama mjamzito. Jumla ya mama wajawazito 350 walihusiswa kwenye utafiti huu, 175 toka kila sehemu yenye malaria ya kwa kiwango cha juu na pia toka kwenye sehemu ya malaria kwa kiwango cha chini. Maambukizo ya malaria kwenye kondo la uzazi ilikuwa 16.6% kwenye eneo la malaria cha kiwango cha juu na 2.3% kwenye eneo lenye malaria kwa kiwango cha chini. Matumizi ya SP yalionyesha uwezekano wa kuzuia maambukizi ya kondo la uzazi hasa eneo lenye malaria ya juu. Kuwa na ujauzito wa kwanza na kuishi eneo lenye malaria ya juu ni kiambata hatarishi cha kupata maambukizo ya kondo la uzazi
Hitimisho: Kwa ujumla matumizi ya dawa kipindi cha ujauzito yapo kwenye kiwangu cha juu, ikiwemo matumizi ya dawa mseto kwenye kipindi cha mimba changa, japokuwa dawa hii siyo chaguo la kwanza kwenye tiba ya malaria kwenye kipindi hichi. Dawa mseto imeonekana kuwa salama zaidi kuliko quinine hivyo ni bora kuanza kufikiria jinsi itakavyoweza kupendekezwa kwa matumizi kipindi cha mimba changa.
Kupitia HDSS imeonyesha inaweza kusaidia kuwa na mfumo wa uhakika na kuaminika wa kukusanya taarifa muhimu za matumizi ya dawa kwa mama mjamzito kwenye nchi masikini. Hivyo ni bora makampuni ya dawa, wafadhili kwa kushirikiana na taasisi za afya ndani na nje ya nchi wafikirie jinsi ya kufadhili mfumo huu ili kusaidia kuboresha takwimu za usalama wa dawa kwa mama wajawazito.
Imethibitika kuwa dawa mseto inapunguwa kwa kiasi kikubwa mwilini mwa mwanamke mjamzito ukilinganisha na mwanamke asiyo mjamzito. Hili huenda ikapelekea mama mjamzito kutopona kwa ufasaa na kupungukiwa uwezekano wa kukabiliyana na maambukizo mapya ya malaria kipindi cha usoni hasa baada ya kumaliza dozi ya malaria. Hivyo tunapendekeza kupitiwa upya dozi ya malaria inayotumika sasa na mama mjamzito na kushauri upatikanaji wa dozi mpya kwa hili kundi la wajawazito.